EP3101009A1 - Ror gamma (rory) modulators - Google Patents

Ror gamma (rory) modulators Download PDF

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Publication number
EP3101009A1
EP3101009A1 EP15170765.0A EP15170765A EP3101009A1 EP 3101009 A1 EP3101009 A1 EP 3101009A1 EP 15170765 A EP15170765 A EP 15170765A EP 3101009 A1 EP3101009 A1 EP 3101009A1
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EP
European Patent Office
Prior art keywords
alkyl
methyl
phenyl
benzamide
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP15170765.0A
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German (de)
French (fr)
Inventor
Joseph Maria Gerardus Barbara Cals
Sander Bernardus NABUURS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Lead Pharma Cel Models IP BV
Original Assignee
Sanofi SA
Lead Pharma Cel Models IP BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi SA, Lead Pharma Cel Models IP BV filed Critical Sanofi SA
Priority to EP15170765.0A priority Critical patent/EP3101009A1/en
Priority to ARP160101634A priority patent/AR104880A1/en
Priority to PCT/EP2016/062701 priority patent/WO2016193461A1/en
Priority to KR1020187000282A priority patent/KR102576004B1/en
Priority to CN201680043482.6A priority patent/CN108430974B/en
Priority to PL16726888T priority patent/PL3303293T3/en
Priority to AU2016273353A priority patent/AU2016273353B2/en
Priority to RU2017145930A priority patent/RU2735546C2/en
Priority to JP2017563090A priority patent/JP6754777B2/en
Priority to US15/579,164 priority patent/US10556866B2/en
Priority to EP16726888.7A priority patent/EP3303293B1/en
Priority to BR112017026223-1A priority patent/BR112017026223B1/en
Priority to PT167268887T priority patent/PT3303293T/en
Priority to MX2017015740A priority patent/MX2017015740A/en
Priority to CA2988002A priority patent/CA2988002C/en
Priority to ES16726888T priority patent/ES2783824T3/en
Publication of EP3101009A1 publication Critical patent/EP3101009A1/en
Priority to IL256038A priority patent/IL256038B/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/23—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
    • C07C311/27—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to modulators of ROR ⁇ , to pharmaceutical compositions comprising the same and to the use of said compounds for the treatment of ROR ⁇ -mediated diseases or conditions, in particular autoimmune diseases and inflammatory diseases.
  • ROR ⁇ t The retinoic-acid-receptor-related orphan receptor ⁇ t (ROR ⁇ t) acts as a master regulator of the development of T H 17 cells, but also as a critical component in non-T H 17 IL-17 producing cells, such as for example ⁇ T-cells.
  • the ROR gene family is part of the nuclear hormone receptor superfamily, and consists of three members (ROR ⁇ , ROR ⁇ and ROR ⁇ ). Each gene is expressed in different isoforms, differing foremost in their N-terminal sequence. Two isoforms of ROR ⁇ have been identified: ROR ⁇ 1 and ROR ⁇ 2 (also known as ROR ⁇ t). The term ROR ⁇ is used here to describe both ROR ⁇ 1 and/or ROR ⁇ 2.
  • the present invention relates to novel compounds according to Formula I or a pharmaceutically acceptable salt thereof wherein:
  • C(1-6)alkyl as used herein means a branched or unbranched alkyl group having 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl. All carbon atoms may optionally be substituted with one or more halogen.
  • C(2-6)alkyl as used herein means a branched or unbranched alkyl group having 2-6 carbon atoms, for example ethyl, propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl. All carbon atoms may optionally be substituted with one or more halogen.
  • C(1-4)alkyl as used herein means an alkyl group having 1-4 carbon atoms, i.e. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. All carbon atoms may optionally be substituted with one or more halogen.
  • C(2-4)alkyl as used herein means an alkyl group having 2-4 carbon atoms, i.e. ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. All carbon atoms may optionally be substituted with one or more halogen.
  • C(1-3)alkyl as used herein means an alkyl group having 1-3 carbon atoms, i.e. methyl, ethyl, propyl or isopropyl. All carbon atoms may optionally be substituted with one or more halogen.
  • C(1-2)alkyl as used herein means an alkyl group having 1-2 carbon atoms i.e. methyl or ethyl. All carbon atoms may optionally be substituted with one or more halogen.
  • C(6-10)aryl as used herein means an aromatic hydrocarbon group having 6-10 carbon atoms, for example phenyl or naphthyl.
  • the preferred aromatic hydrocarbon group is phenyl. All carbon atoms may optionally be substituted with one or more halogen.
  • C(6)aryl as used herein means an aromatic hydrocarbon group having 6 carbon atoms, i.e. phenyl. All carbon atoms may optionally be substituted with one or more halogen.
  • C(6-10)arylC(1-3)alkyl as used herein means an C(6-10)aryl group attached to a C(1-3)alkyl group, both with the same meaning as previously defined.
  • C(6)arylC(1-3)alkyl as used herein means an C(6)aryl group attached to a C(1-3)alkyl group, both with the same meaning as previously defined.
  • heteroatom refers to a nitrogen, sulphur or oxygen atom.
  • C(1-9)heteroaryl as used herein means an aromatic group having 1-9 carbon atoms and 1-4 heteroatoms, which may be attached via a nitrogen atom if feasible, or a carbon atom. Examples include imidazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, furyl, pyrazolyl, isoxazolyl, tetrazolyl and quinolyl. All carbon atoms may optionally be substituted with one or more halogen or methyl.
  • C(1-9)heteroarylC(1-3)alkyl as used herein means an C(1-9)heteroaryl group attached to a C(1-3)alkyl group, both with the same meaning as previously defined.
  • C(3-6)cycloalkyl as used herein means a saturated cyclic hydrocarbon having 3-6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. All carbon atoms may optionally be substituted with one or more halogen or methyl.
  • C(3-5)cycloalkyl as used herein means a saturated cyclic hydrocarbon having 3-5 carbon atoms, i.e. cyclopropyl, cyclobutyl or cyclopentyl. All carbon atoms may optionally be substituted with one or more halogen or methyl.
  • C(3-4)cycloalkyl as used herein means a saturated cyclic hydrocarbon having 3-4 carbon atoms, i.e. cyclopropyl or cyclobutyl. All carbon atoms may optionally be substituted with one or more halogen or methyl.
  • C(3-6)cycloalkylC(1-3)alkyl as used herein means an C(3-6)cycloalkyl group attached to an C(1-3)alkyl group, both with the same meaning as previously defined.
  • An example is cyclopropylmethyl.
  • C(3-5)cycloalkylC(1-3)alkyl as used herein means an C(3-5)cycloalkyl group attached to an C(1-3)alkyl group, both with the same meaning as previously defined.
  • cyclopropylmethyl as used herein means a methyl group substituted with cyclopropyl. All carbon atoms are optionally substituted with one or more halogen or methyl.
  • C(2-5)heterocycloalkyl as used herein means a saturated cyclic hydrocarbon having 2-5 carbon atoms and 1-3 heteroatoms, which may be attached via a nitrogen atom if feasible, or a carbon atom.
  • Examples include piperazinyl, pyrazolidilyl, piperidinyl, morpholinyl and pyrrolidinyl. All carbon atoms may optionally be substituted with one or more halogen or methyl.
  • C(2-5)heterocycloalkylC(1-3)alkyl as used herein means an C(2-5)heterocycloalkyl group attached to an C(1-3)alkyl group, both with the same meaning as previously defined.
  • amino refers to an NH 2 group.
  • (di)C(1-6)alkylamino as used herein means an amino group, which is monosubstituted or disubstituted with a C(1-6)alkyl group, the latter having the same meaning as previously defined
  • (di)C(1-3)alkylamino as used herein means an amino group, which is monosubstituted or disubstituted with a C(1-3)alkyl group, the latter having the same meaning as previously defined.
  • (di)C(1-2)alkylamino as used herein means an amino group, which is monosubstituted or disubstituted with a C(1-2)alkyl group, the latter having the same meaning as previously defined.
  • An example is dimethylamino.
  • (di)C(3-6)cycloalkylamino as used herein means an amino group, which is monosubstituted or disubstituted with a C(3-6)cycloalkyl group, the latter having the same meaning as previously defined.
  • An example is cyclopropylamino.
  • (di)C(3-4)cycloalkylamino as used herein means an amino group, which is monosubstituted or disubstituted with a C(3-4)cycloalkyl group, the latter having the same meaning as previously defined.
  • cyclopropylamino means an amino group substituted with cyclopropyl. All carbon atoms may optionally besubstituted with one or more halogen or methyl.
  • (di)(C(3-6)cycloalkylC(1-3)alkyl)amino as used herein means an amino group, which is monosubstituted or disubstituted with a C(3-6)cycloalkylC(1-3)alkyl group as previously defined.
  • C(1-3)alkoxy means an alkoxy group having 1-3 carbon atoms, the alkyl moiety being branched or unbranched. All carbon atoms are optionally substituted with one or more F.
  • C(1-2)alkoxy means an alkoxy group having 1-2 carbon atoms. Preferred is methoxy. All carbon atoms may optionally be substituted with one or more F.
  • halogen as used herein means Cl or F.
  • the attachment point is at the last group.
  • substituted means that one or more hydrogens on the designated atom/atoms is/are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Stable compound or “stable structure” is defined as a compound or structure that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • pharmaceutically acceptable salt represents those salts which are, within the scope of medical judgment, suitable for use in contact for the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • the free base function may be obtained during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable mineral acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like.
  • the acid function can be reacted with an organic or a mineral base, like sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • distinguished compounds are those of Formula I in which :
  • distinguished compounds are those of Formula I in which :
  • distinguished compounds are those of Formula I in which :
  • distinguished compounds are those of Formula I in which :
  • distinguished compounds are those of Formula I in which :
  • distinguished compounds are those of Formula I in which :
  • distinguished compounds are those of Formula I in which :
  • the invention also relates to a compound according to Formula I wherein R, is C(1-4)alkyl, C(3-5)cycloalkylC(1-3)alkyl or (di)C(3-4)cycloalkylamino.
  • the invention also relates to a compound according to Formula I wherein R 1 is C(2-4)alkyl or C(3-5)cycloalkylC(1-3)alkyl.
  • the invention also relates to a compound according to Formula I wherein R 1 is (di)C(3-4)cycloalkylamino.
  • the invention relates to a compound according to Formula I wherein R 1 is ethyl or cyclopropylmethyl.
  • the invention relates to a compound according to Formula I wherein R 1 is ethyl.
  • the invention relates to a compound according to Formula I wherein R 1 is cyclopropylamino.
  • the invention relates to a compound according to Formula I wherein R 1 is cyclopropylmethyl.
  • the invention also relates to a compound according to Formula I wherein R 2 and R 3 independently are H or methyl.
  • the invention relates to a compound according to Formula I wherein R 2 and R 3 independently are H.
  • the invention also relates to a compound according to Formula I wherein R 4 is H.
  • the invention also relates to a compound according to Formula I wherein R 5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)arylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano;
  • R 5 in Formula I is H, C(1-6)alkyl or C(6-10)arylC(1-3)alkyl.
  • R 5 in Formula I is H, methyl, ethyl, propyl, isopropyl, butyl or benzyl.
  • R 5 in Formula I is H.
  • R 5 in Formula I is C(1-6)alkyl.
  • R 5 in Formula I is C(6-10)arylC(1-3)alkyl.
  • the invention also relates to a compound according to Formula I wherein one of the groups R 7 , R 8 , Rg is the sulfonyl group with R 1 attached to it and the others including R 6 and R 10 are independently H or C(1-6)alkyl.
  • the sulfonyl group is represented by R 8 , i.e. the sulfonyl group is attached at the para position of the aryl ring.
  • the invention also relates to a compound according to Formula I wherein R 11 -R 14 are independently H, halogen, methyl or methoxy.
  • the invention relates to a compound according to Formula I wherein R 11 -R 14 are independently H or methyl.
  • the invention relates to a compound according to Formula I wherein A 11 -A 14 are carbon atoms.
  • the invention relates to a compound according to Formula I -wherein A 11 or A 14 is nitrogen, the remaining position A is CR 11 or CR 14 .
  • the invention also relates to a compound according to Formula I wherein
  • R 15 is C(1)alkyl substituted with one or more F or R 15 is C(2-6)alkyl optionally substituted with one or more F; and R 16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F.
  • the invention relates to a compound according to Formule I wherein R 15 is C(1)alkyl substituted with one or more F or R 15 is C(2-6)alkyl optionally substituted with one or more F; and R 16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(6-10)aryl or C(6-10)arylC(1-3)alkyl, all groups optionally substituted with one or more F.
  • the invention relates to a compound according to Formule I wherein R 15 is CF 3 ; and R 16 is methyl, CHF 2 , CF 3 , ethyl, 2,2-dimethylpropyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopentyl, phenyl or benzyl.
  • the invention relates to a compound according to Formula I wherein both R 15 and R 16 is CF 3 .
  • the invention relates to a compound according to Formula I wherein either R 15 or R 16 is CF 3 .
  • the invention relates to a compound according to Formula I wherein R 15 is CF 3 and R 16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(6-10)aryl or C(6-10)arylC(1-3)alkyl, all groups optionally substituted with one or more F.
  • the invention relates to a compound according to Formula I wherein R 15 is CF 3 and R 16 is methyl, CHF 2 , CF 3 , ethyl, 2,2-dimethylpropyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopentyl, phenyl or benzyl.
  • the invention relates to a compound according to Formula I wherein R 15 is CF 3 and R 16 is C(1-6)alkyl, with all carbon atoms of the alkyl group optionally substituted with one or more F.
  • the invention relates to a compound according to Formula I wherein R 15 is CF 3 and R 16 is methyl, CHF 2 , CF 3 , ethyl, 2,2-dimethylpropyl, propyl, isopropyl, butyl, isobutyl.
  • the invention relates to a compound according to Formula I wherein R 15 is CF 3 and R 16 is C(3-6)cycloalkyl.
  • the invention relates to a compound according to Formula I wherein R 15 is CF 3 and R 16 is cyclopropyl or cyclopentyl.
  • the invention relates to a compound according to Formula I wherein R 15 is CF 3 and R 16 is C(6-10)aryl.
  • the invention relates to a compound according to Formula I wherein R 15 is CF 3 and R 16 is phenyl.
  • the invention relates to a compound according to Formula I wherein R 15 is CF 3 and R 16 is or C(6-10)arylC(1-3)alkyl.
  • the invention relates to a compound according to Formula I wherein R 15 is CF 3 and R 16 is benzyl.
  • the invention also relates to a compound according to Formula I wherein R 5 is H and R 15 is CF 3 and R 16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(6-10)aryl or C(6-10)arylC(1-3)alkyl.
  • the invention relates to a compound according to Formula I wherein R 5 is H, R 15 is CF 3 and R 16 is C(1-6)alkyl, with all carbon atoms of the alkyl group optionally substituted with one or more F.
  • the invention relates to a compound according to Formula I wherein R 5 is H, R 15 is CF 3 and R 16 is methyl, CHF 2 , CF 3 , ethyl, 2,2-dimethylpropyl, propyl, isopropyl, butyl, isobutyl.
  • the invention relates to a compound according to Formula I wherein R 5 is H and both R 15 and R 16 are CF 3 .
  • the invention relates to a compound according to Formula I wherein R 5 is H, R 15 is CF 3 and R 16 is C(6-10)aryl, phenyl being the most preferred.
  • the invention relates to a compound according to Formula I wherein R 5 is H, R 15 is CF 3 and R 16 is C(3-6)cycloalkyl.
  • the invention relates to a compound according to Formula I wherein R 5 is H, R 15 is CF 3 and R 16 is cyclopropyl or cyclopentyl.
  • the invention relates to a compound according to Formula I wherein R 5 is H, R 15 is CF 3 and R 16 is C(6-10)arylC(1-3)alkyl.
  • the invention relates to a compound according to Formula I
  • R 5 is H
  • R 15 is CF 3
  • R 16 is benzyl
  • the invention also relates to those compounds wherein all specific definitions for A 11 through A 14 , R 1 through R 16 , and all substituent groups in the various aspects of the inventions defined here above occur in any combination within the definition of the compound of Formula I .
  • the invention relates to compounds of Formula I which have a pIC50 of 5 or higher. In yet another aspect the invention relates to compounds according to Formula I with a pIC50 of more than 6. In yet another aspect the invention relates to compounds according to Formula I with a pIC50 of more than 7.
  • the invention resides in the compounds according to Formula I selected as described in examples 1 - 35 .
  • N° Structure IUPAC name 1 N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)propyl]benzamide 2 N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)benzamide 3 N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(1-hydroxy-1-methyl-ethyl)benzamide 4 N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide 5 N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[
  • the compounds of Formula I can form salts, which are also within the scope of this invention.
  • Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the compounds of Formula I may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula I as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g. hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g. chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • Enantiomers can also be separated by use of chiral HPLC column.
  • IC50 values are dependent on the compound tested.
  • a compound with an IC50 value less than 10 -5 M is generally considered a candidate for drug selection.
  • this value is lower than 10 -6 M.
  • a compound which has a higher IC50 value, but is selective for the particular receptor may be even a better candidate.
  • the compounds of the invention inhibit ROR ⁇ activity. Modulation of ROR ⁇ activity can be measured using for example biophysical (natural) ligand displacement studies, biochemical AlphaScreen or FRET assays, cellular GAL4 reporter gene assays, cellular IL-17 promotor reporter assay or functional IL-17 ELISA assays using for example mouse splenocytes or human peripheral blood mononuclear cells (PBMCs) cultured under T H 17 polarizing conditions.
  • PBMCs peripheral blood mononuclear cells
  • the interaction of a ligand with ROR ⁇ can be determined by measuring, for example, the ligand modulated interaction of cofactor-derived peptides with the ROR ⁇ ligand binding domain, or measuring the gene products of ligand modulated ROR ⁇ mediated transcription using, for example, luciferase reporter assays or IL-17 ELISA assays.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising compounds or pharmaceutically acceptable salts thereof having the general Formula I in admixture with pharmaceutically acceptable excipients and optionally other therapeutic agents.
  • the excipients must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • the invention further includes a compound of Formula I in combination with one or more other drug(s).
  • compositions include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, topical, nasal, local or rectal administration, and the like, all in unit dosage forms for administration.
  • the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like.
  • the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use.
  • sterile liquid carrier e.g. water
  • the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
  • the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
  • Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
  • aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.
  • the invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.
  • the exact dose and regimen of administration of the active ingredient, or a pharmaceutical composition thereof, may vary with the particular compound, the route of administration, and the age and condition of the individual subject to whom the medicament is to be administered.
  • a dosage for humans preferably contains 0.0001-100 mg per kg body weight.
  • the desired dose may be presented as one dose or as multiple sub-doses administered at appropriate intervals throughout the day.
  • the compounds according to the invention can be used in therapy.
  • a further aspect of the invention resides in the use of compounds according to the invention or a pharmaceutically acceptable salt thereof for the treatment of ROR ⁇ -mediated diseases or ROR ⁇ mediated conditions.
  • the compounds according to the invention can be used in as medicament.
  • Another aspect of the invention resides in the use of compounds having the general Formula I or a pharmaceutically acceptable salt thereof for the treatment of autoimmune diseases, in particular those diseases in which Th17 cells and non-Th17 cells, which express Th17 hallmark cytokines play a prominent role.
  • autoimmune diseases in particular those diseases in which Th17 cells and non-Th17 cells, which express Th17 hallmark cytokines play a prominent role.
  • These include, but are not limited to, the treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn's disease and multiple sclerosis.
  • compounds having the general Formula I or a pharmaceutically acceptable salt thereof can be used for treatment of inflammatory diseases in which Th17 cells and/or non-Th17 cells, which express Th17 hallmark cytokines play a prominent role such as, but not limited to respiratory diseases, osteoarthritis and asthma.
  • compounds or a pharmaceutically acceptable salt thereof having the general Formula I can be used for treatment of infectious diseases in which Th17 cells and/or non-Th17 cells, which express Th17 hallmark cytokines play a prominent role such as, but not limited to mucosal leishmaniasis.
  • Compounds having the general Formula I or a pharmaceutically acceptable salt thereof can also be used for treatment of other diseases in which Th17 cells and/or non-Th17 cells, which express Th17 hallmark cytokines play a prominent role such as, but not limited to Kawaski disease and Hashimoto's thyroiditis.
  • the invention resides in the use of compounds having the general Formula I for the treatment of multiple sclerosis, inflammatory bowel disease, Crohn's disease, psoriasis, rheumatoid arthritis, asthma, osteoarthritis, Kawaski disease, Hashimoto's thyroiditis, cancer and mucosal leishmaniasis.
  • the compounds according to the invention can be used in therapies to treat or prevent multiple sclerosis, inflammatory bowel disease, Crohn's disease, psoriasis and rheumatoid arthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, cancer and mucosal leishmaniasis.
  • the compounds according to the invention can be used to treat or prevent psoriasis.
  • the compounds according to the invention can be used to treat inflammatory bowel disease.
  • the compounds described herein, including compounds of general Formula I, building blocks II , III , IV and V can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. Many of the reactions can also be carried out under microwave conditions or using conventional heating or utilizing other technologies such as solid phase reagents/scavengers or flow chemistry. For example, hydrogenation reactions can be performed using a continuous flow chemistry apparatus such as the H-Cube Pro ® from ThalesNano Nanotechnology company in Budapest, Hungary. In these reactions, it is also possible to make use of variants which are themselves known to those skilled in the art, but are not mentioned in greater detail.
  • the compounds can be purified by using any of the methods of purification of organic compounds, for example, crystallization or silica gel or alumina column chromatography, using different solvents in suitable ratios. All possible stereoisomers are envisioned within the scope of the invention. In the discussion below variables have the meaning indicated above unless otherwise indicated.
  • HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • DMF Dimethylformamide
  • DiPEA Diisopropylethylamine
  • DMAP 4-(dimethylamino)pyridine
  • CH 2 Cl 2 DCM: dichloromethane
  • DCC N,N'-Dicyclohexylcarbodiimide
  • mCPBA 3-chloroperoxybenzoic acid
  • TFA Trifluoroacetic acid
  • TFAA Trifluoroacetic anhydride
  • THF Tetrahydrofuran; cont.: continuous
  • DMSO Dimethylsulfoxide
  • PTSA p-Toluenesulfonic acid
  • PyBOP (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
  • EtOH EtOH:
  • Chemical names are preferred IUPAC names, generated using Accelrys Draw 4.1.
  • the derivatives of the invention having Formula I can be prepared by methods known in the art of organic chemistry.
  • Compounds of the invention can for example be obtained by an amide coupling reaction between an amine derivative of building block II , wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , Rg and R 10 are as defined for compound Formula I and a carboxylic acid derivative of building block III (X 1 is OH), wherein R 5 , R 15 , R 16 , A 11 , A 12 , A 13 and A 14 are as defined for compound of Formula I , using a coupling reagent such as EDCI, HATU, DCC, or PyBOP or the like, in the presence of a suitable base such as DiPEA or DMAP.
  • a coupling reagent such as EDCI, HATU, DCC, or PyBOP or the like
  • the carboxylic acid derivative of building block III OH
  • Scheme 2 demonstrates an alternative route for the preparation of derivatives of Formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , F 10 , R 15 , R 16 , A 11 , A 12 , A 13 and A 14 are as defined for compounds of Formula I.
  • the reaction is performed by heating the mixture in a polar solvent such as DMSO, DMF or the like at temperature between 80 and 140°C using microwave or conventional heating conditions.
  • Scheme 3 illustrates general methods for the preparation of building blocks II wherein R 1 , R 6 , R 7 , Rg and R 10 are as defined for compounds of Formula I.
  • 4-mercapto-2-methylbenzonitrile derivatives 3 can be alkylated in the presence of a suitable base such as potassium carbonate to give the corresponding thioether derivatives 4 .
  • Scheme 4 illustrates a general reaction scheme for the preparation of building blocks II wherein R 1 is (di)C(3-6)cycloalkylamino or (di)(C(3-6)cycloalkylC(1-3)alkyl)amino as previously described and R 6 , R 7 , Rg and R 10 are as defined for compounds of Formula I.
  • Scheme 5 illustrates a general reaction scheme for the preparation of building blocks III wherein R 15 is CF 3 and R 5 , R 16 , A 11 , A 12 , A 13 and A 14 are as defined for compounds of Formula I.
  • Ketone derivatives 7 wherein R is H or lower alkyl such as methyl or ethyl can be treated with TMSCF 3 and TBAF to give the corresponding alcohol derivatives 8 , which can be hydrolyzed by a hydroxide source such as NaOH to obtain building blocks III wherein R 15 is CF 3 , R 5 is H and R 16 , A 11 , A 12 , A 13 and A 14 are as previously described.
  • a hydroxide source such as NaOH
  • Alcohol derivatives 8 can be alkylated with a suitable alkyl halide in presence of a base such as potassium carbonate, sodium hydride or the like to give ether derivatives 9 which can then be hydrolyzed to building blocks III wherein R 15 is CF 3 and R 5 , R 16 , A 11 , A 12 , A 13 and A 14 with the proviso that R 5 is not H.
  • a base such as potassium carbonate, sodium hydride or the like
  • Some of the building blocks III used in the examples of general Formula I are commercially available, known or prepared according to methods known to those skilled in the art.
  • the building blocks IV can be prepared by an amide coupling reaction between an amine derivative 10, wherein R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 are as previously described and X 2 is Br or I and a carboxylic acid derivative of building block III, wherein R 5 , R 15 , R 16 , A 11 , A 12 , A 13 and A 14 are as defined for compounds of Formula I, using a coupling reagent such as EDCI, HATU, DCC, or PyBOP or the like, in the presence of a suitable base such as DiPEA or DMAP.
  • a coupling reagent such as EDCI, HATU, DCC, or PyBOP or the like
  • Scheme 7 shows a general reaction scheme for the preparation of building blocks V wherein R 1 has the meaning as previously described.
  • Sulfonyl chlorides 11 can be converted to sodium sulfinate derivatives of building block V by treatment with sodium sulfite in water in the presence of a suitable base such as sodium bicarbonate.
  • building blocks V are commercially available, known or prepared according to methods known to those skilled in the art.
  • III-1 4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)benzoic acid.
  • III-2 4-[1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]benzoic acid.
  • III-3 4-[1-hydroxy-1-(trifluoromethyl)propyl]benzoic acid.
  • III-4 4-[1-hydroxy-1-(trifluoromethyl)butyl]benzoic acid.
  • III-6 4-[1-hydroxy-3-methyl-1-(trifluoromethyl)butyl]benzoic acid.
  • III-7 4-[1-hydroxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzoic acid.
  • III-8 4-[1-hydroxy-2-methyl-1-(trifluoromethyl)propyl]benzoic acid.
  • III-11 4-(2,2,2-trifluoro-1-hydroxy-1-phenyl-ethyl)benzoic acid.
  • III-13 3-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzoic acid.
  • III-15 4-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzoic acid.
  • III-16 4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]benzoic acid.
  • IV-1 N-[(1 R)-1-(4-bromophenyl)ethyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide.
  • IV-2 N-[(1S)-1-(4-bromophenyl)ethyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide.
  • V-1 Sodium cyclopropylmethanesulfinate.
  • Example inhibitors 1-35 were tested for their ability to inhibit ROR ⁇ activity in a ROR ⁇ GAL4 reporter gene assay. The assay procedure and results are described below.
  • a GAL4 one-hybrid reporter system employing luciferase readout was established to determine inhibition of ROR ⁇ in 293FT cells.
  • the ROR ⁇ ligand-binding domain (LBD) was fused to the yeast GAL4 DNA binding domain (DBD) and placed under the control of the human cytomegalovirus (CMV) immediate early promoter, using expression vector pFN26A (Promega) and standard recombinant DNA cloning methods.
  • CMV human cytomegalovirus
  • pFN26A Promega
  • a similar vector was generated in which the GAL4-DBD was fused to Herpes simplex virus protein 16 (VP16), a constitutive transcriptional activator.
  • VP16 Herpes simplex virus protein 16
  • the pGL4.35 vector contains nine copies of the GAL4 Upstream Activator Sequence (UAS). This sequence drives the transcription of the luciferase reporter gene luc2P in response to binding of a fusion protein containing the GAL4 DNA binding domain, as for example expressed by the GAL4-ROR ⁇ -LBD and GAL4-VP16 expression vectors described above.
  • UAS GAL4 Upstream Activator Sequence
  • This sequence drives the transcription of the luciferase reporter gene luc2P in response to binding of a fusion protein containing the GAL4 DNA binding domain, as for example expressed by the GAL4-ROR ⁇ -LBD and GAL4-VP16 expression vectors described above.
  • the pGL4.35 expression vector and the appropriate GAL4 fusion protein expression vector were bulk transfected in the 293FT cells using standard transfection techniques.
  • 293FT cells (Invitrogen) were transfected with a GAL4 fusion protein expression vector (as described above) and the transcriptional reporter construct (pGL4.35, Promega).
  • 60 ⁇ L of Trans IT-293 transfection reagent (Mirus Bio) was added drop wise to 1500 ⁇ l Opti-MEM I Reduced Serum Medium (Invitrogen) and incubated at RT (RT) for 5 to 20 minutes.
  • 1500 ⁇ L of this reagent mixture was added to 5 ⁇ g of GAL4 fusion protein expression vector and 5 ⁇ g of the transcriptional reporter construct, and incubated at RT for 20 minutes.
  • the cells were harvested (as described above) and counted. 13x10 6 cells were spun down, the supernatant was aspirated and the cells were re-suspended in 17.3 mL of assay medium obtaining a cell suspension of 0.75x10 6 cells/mL. 80 ⁇ L of cell suspension (60,000 cells) was plated per well into a white, flat bottom, tissue culture treated, 96 well screening plates (Greiner).
  • Test compounds were diluted, starting from a 10 mM dimethylsulfoxide (DMSO) stock solution, to serial dilutions in DMSO at 500x the final test concentration. Subsequently, these solutions were diluted to 5x the final test concentration in two 10-fold-dilution steps in assay medium. The final DMSO concentration of the 5x test compound solution was 1%. 20 ⁇ L of the 5x test compound solution was added to each test well of the 96 well plate previously plated with 80 ⁇ l cell suspension, resulting in the final test concentration with 0.2% DMSO.
  • DMSO dimethylsulfoxide
  • the plates were incubated overnight (16-24 hours) at 37 °C and 5% CO 2 .
  • the luciferase readout the luciferase reagent (Britelite Plus, Perkin Elmer) was brought to RT. To each test well of the screening plates, 100 ⁇ L of 2.5-fold diluted Britelite Plus reagent was added, followed by incubation at RT for 10 minutes. The luciferase luminescence signal was measured using a Wallac Victor Microplate Reader (Perkin Elmer).
  • IC 50 half maximum inhibitory concentration
  • example 3 as a pIC50 below 5.
  • PBMC Peripheral blood mononuclear cell
  • Example inhibitor 5 was tested for its ability to inhibit the IL-17A production in anti-CD3/anti-CD28 stimulated peripheral blood mononuclear cells (PBMCs) isolated from human blood. The assay procedure and results are described below.
  • PBMCs peripheral blood mononuclear cells
  • This assay is designed to measure the levels of IL-17A secreted from anti-CD3/anti-CD28 stimulated PBMCs with the aim of measuring ROR ⁇ mediated inhibition of IL-17A production.
  • the assay medium consists of 90% RPMI 1640 (Lonza), 10% heat inactivated fetal bovin serum (FBS, Lonza) and 100 U/mL penicillin/streptomycin solution.
  • Anti-CD3 antibody (BD Pharmingen) was diluted to 10 ⁇ g/ml in PBS (Lonza). 30 ⁇ L of 10 ⁇ g/ml anti-CD3 solution was added to the inner 60 wells, excluding any negative control wells, of a 96-well cell culture treated U-bottom plate (Greiner). Plates were incubated overnight (16-24 hours) at 37 °C and 5% CO 2 .
  • Peripheral blood mononuclear cells were separated from buffy coats (Sanquin) using Ficoll-Paque PREMIUM separation medium (GE Healthcare Life Sciences) according to manufacturer's protocol and re-suspended in assay medium at 37 °C.
  • Test compounds were diluted, starting from a 10 mM dimethylsulfoxide (DMSO) stock solution, to serial dilutions in DMSO at 200x the final test concentration. Subsequently, these solutions were diluted in two dilution steps in assay medium to 10x the final test concentration. The DMSO concentration of the 10x test compound solution was 5%.
  • DMSO dimethylsulfoxide
  • Anti-CD28 antibody (BD Pharmingen) was diluted to 20 ⁇ g/mL in PBS.
  • the PBMCs were diluted to a concentration of 2.5x10 6 cells/mL in assay medium at 37 °C.
  • the anti-CD3 coated plates were washed three times with PBS, the wells were subsequently aspirated using vacuum.
  • IL-17A levels in the supernatants was determined using an IL-17 ELISA kit (human IL-17 DuoSet, R&D systems) according to manufacturer's protocol.
  • IC 50 half maximum inhibitory concentration
  • the tested example 5 was found to have a mean pIC 50 value equal to 7.

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Abstract

The present invention relates to novel compounds according to Formula I or a pharmaceutically acceptable salt thereof wherein the variables are as defined in the claims. The compounds can be used as inhibitors of RORγ and are useful for the treatment of RORγ mediated diseases.

Description

  • The present invention relates to modulators of RORγ, to pharmaceutical compositions comprising the same and to the use of said compounds for the treatment of RORγ-mediated diseases or conditions, in particular autoimmune diseases and inflammatory diseases.
  • The retinoic-acid-receptor-related orphan receptor γt (RORγt) acts as a master regulator of the development of TH17 cells, but also as a critical component in non-TH17 IL-17 producing cells, such as for example γδ T-cells. The ROR gene family is part of the nuclear hormone receptor superfamily, and consists of three members (RORα, RORβ and RORγ). Each gene is expressed in different isoforms, differing foremost in their N-terminal sequence. Two isoforms of RORγ have been identified: RORγ1 and RORγ2 (also known as RORγt). The term RORγ is used here to describe both RORγ1 and/or RORγ2.
  • The present invention relates to novel compounds according to Formula I
    Figure imgb0001
     or a pharmaceutically acceptable salt thereof wherein:
    • A11 - A14 are N or CR11, CR12, CR13, CR14, respectively, with the proviso that no more than two of the four positions A can be simultaneously N;
    • R1 is C(2-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, (di)C(3-6)cycloalkylamino or (di)(C(3-6)cycloalkylC(1-3)alkyl)amino, with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl;
    • R2 and R3 are independently H, F, methyl, ethyl, hydroxy, methoxy or R2 and R3 together is carbonyl, all alkyl groups, if present, optionally being substituted with one or more F;
    • R4 is H or C(1-6)alkyl;
    • R5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl,
    • C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(3-6)cycloalkyl,
    • C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, Cl, C(1-2)alkyl,
    • C(1-2)alkoxy or cyano ;
    • the sulfonyl group with R1 is represented by one of R7, R8 or R9;
    • the remaining R6-R14 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl, all of the alkyl groups optionally being substituted with one or more F;
    • R15 is H, C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F, Cl, C(1-2)alkyl, C(1-2)alkoxy or cyano;
    • and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F, Cl, C(1-2)alkyl, C(1-2)alkoxy or cyano.
  • The term C(1-6)alkyl as used herein means a branched or unbranched alkyl group having 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl. All carbon atoms may optionally be substituted with one or more halogen.
  • The term C(2-6)alkyl as used herein means a branched or unbranched alkyl group having 2-6 carbon atoms, for example ethyl, propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl. All carbon atoms may optionally be substituted with one or more halogen. The term C(1-4)alkyl as used herein means an alkyl group having 1-4 carbon atoms, i.e. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. All carbon atoms may optionally be substituted with one or more halogen.
  • The term C(2-4)alkyl as used herein means an alkyl group having 2-4 carbon atoms, i.e. ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. All carbon atoms may optionally be substituted with one or more halogen.
  • The term C(1-3)alkyl as used herein means an alkyl group having 1-3 carbon atoms, i.e. methyl, ethyl, propyl or isopropyl. All carbon atoms may optionally be substituted with one or more halogen.
  • The term C(1-2)alkyl as used herein means an alkyl group having 1-2 carbon atoms i.e. methyl or ethyl. All carbon atoms may optionally be substituted with one or more halogen.
  • The term C(6-10)aryl as used herein means an aromatic hydrocarbon group having 6-10 carbon atoms, for example phenyl or naphthyl. The preferred aromatic hydrocarbon group is phenyl. All carbon atoms may optionally be substituted with one or more halogen.
  • The term C(6)aryl as used herein means an aromatic hydrocarbon group having 6 carbon atoms, i.e. phenyl. All carbon atoms may optionally be substituted with one or more halogen.
  • The term C(6-10)arylC(1-3)alkyl as used herein means an C(6-10)aryl group attached to a C(1-3)alkyl group, both with the same meaning as previously defined.
  • The term C(6)arylC(1-3)alkyl as used herein means an C(6)aryl group attached to a C(1-3)alkyl group, both with the same meaning as previously defined.
  • The term heteroatom as used herein refers to a nitrogen, sulphur or oxygen atom.
  • The term C(1-9)heteroaryl as used herein means an aromatic group having 1-9 carbon atoms and 1-4 heteroatoms, which may be attached via a nitrogen atom if feasible, or a carbon atom. Examples include imidazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, furyl, pyrazolyl, isoxazolyl, tetrazolyl and quinolyl. All carbon atoms may optionally be substituted with one or more halogen or methyl.
  • The term C(1-9)heteroarylC(1-3)alkyl as used herein means an C(1-9)heteroaryl group attached to a C(1-3)alkyl group, both with the same meaning as previously defined. The term C(3-6)cycloalkyl as used herein means a saturated cyclic hydrocarbon having 3-6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. All carbon atoms may optionally be substituted with one or more halogen or methyl.
  • The term C(3-5)cycloalkyl as used herein means a saturated cyclic hydrocarbon having 3-5 carbon atoms, i.e. cyclopropyl, cyclobutyl or cyclopentyl. All carbon atoms may optionally be substituted with one or more halogen or methyl.
  • The term C(3-4)cycloalkyl as used herein means a saturated cyclic hydrocarbon having 3-4 carbon atoms, i.e. cyclopropyl or cyclobutyl. All carbon atoms may optionally be substituted with one or more halogen or methyl.
  • The term C(3-6)cycloalkylC(1-3)alkyl as used herein means an C(3-6)cycloalkyl group attached to an C(1-3)alkyl group, both with the same meaning as previously defined. An example is cyclopropylmethyl.
  • The term C(3-5)cycloalkylC(1-3)alkyl as used herein means an C(3-5)cycloalkyl group attached to an C(1-3)alkyl group, both with the same meaning as previously defined.
  • The term cyclopropylmethyl as used herein means a methyl group substituted with cyclopropyl. All carbon atoms are optionally substituted with one or more halogen or methyl.
  • The term C(2-5)heterocycloalkyl as used herein means a saturated cyclic hydrocarbon having 2-5 carbon atoms and 1-3 heteroatoms, which may be attached via a nitrogen atom if feasible, or a carbon atom. Examples include piperazinyl, pyrazolidilyl, piperidinyl, morpholinyl and pyrrolidinyl. All carbon atoms may optionally be substituted with one or more halogen or methyl.
  • The term C(2-5)heterocycloalkylC(1-3)alkyl as used herein means an C(2-5)heterocycloalkyl group attached to an C(1-3)alkyl group, both with the same meaning as previously defined.
  • The term amino as used herein refers to an NH2 group.
  • The term (di)C(1-6)alkylamino as used herein means an amino group, which is monosubstituted or disubstituted with a C(1-6)alkyl group, the latter having the same meaning as previously defined
  • It is to be understood that in the (di)C(1-6)alkylamino groups containing two C(1-6)alkyl groups, one of the C(1-6)alkyl groups can be replaced by a C(3-6)cycloalkyl group as previously defined.
  • The term (di)C(1-3)alkylamino as used herein means an amino group, which is monosubstituted or disubstituted with a C(1-3)alkyl group, the latter having the same meaning as previously defined.
  • The term (di)C(1-2)alkylamino as used herein means an amino group, which is monosubstituted or disubstituted with a C(1-2)alkyl group, the latter having the same meaning as previously defined. An example is dimethylamino.
  • The term (di)C(3-6)cycloalkylamino as used herein means an amino group, which is monosubstituted or disubstituted with a C(3-6)cycloalkyl group, the latter having the same meaning as previously defined. An example is cyclopropylamino.
  • The term (di)C(3-4)cycloalkylamino as used herein means an amino group, which is monosubstituted or disubstituted with a C(3-4)cycloalkyl group, the latter having the same meaning as previously defined.
  • The term cyclopropylamino means an amino group substituted with cyclopropyl. All carbon atoms may optionally besubstituted with one or more halogen or methyl.
  • The term (di)(C(3-6)cycloalkylC(1-3)alkyl)amino as used herein means an amino group, which is monosubstituted or disubstituted with a C(3-6)cycloalkylC(1-3)alkyl group as previously defined.
  • It is to be understood that in the (di)(C(3-6)cycloalkylC(1-3)alkyl)amino groups containing two C(3-6)cycloalkylC(1-3)alkyl groups, one of the C(3-6)cycloalkylC(1-3)alkyl groups can be replaced by a C(1-6)alkyl or a C(3-6)cycloalkyl group, both as previously defined.
  • The term C(1-3)alkoxy means an alkoxy group having 1-3 carbon atoms, the alkyl moiety being branched or unbranched. All carbon atoms are optionally substituted with one or more F.
  • The term C(1-2)alkoxy means an alkoxy group having 1-2 carbon atoms. Preferred is methoxy. All carbon atoms may optionally be substituted with one or more F.
  • The term halogen as used herein means Cl or F.
  • In the above definitions with multifunctional groups, the attachment point is at the last group.
  • When, in the definition of a substituent, is indicated that "all of the alkyl groups" of said substituent are optionally substituted, this also includes the alkyl moiety of an alkoxy group.
  • The term "substituted" means that one or more hydrogens on the designated atom/atoms is/are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. "Stable compound" or "stable structure" is defined as a compound or structure that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
  • The term pharmaceutically acceptable salt represents those salts which are, within the scope of medical judgment, suitable for use in contact for the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. They may be obtained during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable mineral acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like. The acid function can be reacted with an organic or a mineral base, like sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • According to the present invention, distinguished compounds are those of Formula I in which :
    • A11 - A14 are N or CR11, CR12, CR13, CR14, respectively, with the proviso that no more than two of the four positions A can be simultaneously N;
    • R1 is C(2-6)alkyl, C(3-6)cycloalkylC(1-3)alkyl or (di)C(3-6)cycloalkylamino, with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl;
    • R2 and R3 are independently H, methyl, or R2 and R3 together is carbonyl, all alkyl groups, if present, optionally being substituted with one or more F;
    • R4 is H;
    • R5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)arylC(1-3)alkyl,
    • C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano ;
    • the sulfonyl group with R1 is represented by R8 ;
    • the remaining R6-R14 are independently H, halogen, C(1-3)alkoxy or C(1-6)alkyl, all of the alkyl groups optionally being substituted with one or more F;
    • R15 is C(1)alkyl substituted with one or more F or R15 is C(2-6)alkyl optionally substituted with one or more F;
    • and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F.
  • According to the present invention, distinguished compounds are those of Formula I in which :
    • A11 - A14 is CR11, CR12, CR13, CR14;
    • R1 is C(2-6)alkyl, C(3-6)cycloalkylC(1-3)alkyl or (di)C(3-6)cycloalkylamino, with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl;
    • R2 and R3 are independently H, methyl, or R2 and R3 together is carbonyl, all alkyl groups, if present, optionally being substituted with one or more F;
    • R4 is H;
    • R5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)arylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano ;
    • the sulfonyl group with R1 is represented by R8 ;
    • the remaining R6-R14 are independently H, halogen, C(1-3)alkoxy or C(1-6)alkyl, all of the alkyl groups optionally being substituted with one or more F;
    • R15 is C(1)alkyl substituted with one or more F or R15 is C(2-6)alkyl optionally substituted with one or more F;
    • and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F.
  • According to the present invention, distinguished compounds are those of Formula I in which :
    • one or two positions A in A11 - A14 are N, the remaining positions A in A11-A14 are CR11, CR12, CR13 or CR14, respectively;
    • R1 is C(2-6)alkyl, C(3-6)cycloalkylC(1-3)alkyl or (di)C(3-6)cycloalkylamino, with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl;
    • R2 and R3 are independently H, methyl, or R2 and R3 together is carbonyl;
    • R4 is H;
    • R5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)arylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano ;
    • the sulfonyl group with R1 is represented by R8 ;
    • the remaining R6-R14 are independently H, halogen, C(1-3)alkoxy or C(1-6)alkyl, all of the alkyl groups optionally being substituted with one or more F;
    • R15 is C(1-6)alkyl, all alkyl groups optionally substituted with one or more F;
    • and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F.
  • According to the present invention, distinguished compounds are those of Formula I in which :
    • A11 - A14 is CR11, CR12, CR13, CR14;
    • R1 is C(2-6)alkyl, C(3-6)cycloalkylC(1-3)alkyl, (di)C(3-6)cycloalkylamino;
    • R2 and R3 are independently H or methyl;
    • R4 is H;
    • R5 is H, C(1-6)alkyl or C(6-10)arylC(1-3)alkyl;
    • the sulfonyl group with R1 is represented by R8 ;
    • the remaining R6-R14 are independently H or C(1-6)alkyl;
    • R15 is C(1)alkyl substituted with one or more F or R15 is C(2-6)alkyl optionally substituted with one or more F;
    • and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(6-10)aryl or C(6-10)arylC(1-3)alkyl, all groups optionally substituted with one or more F.
  • According to the present invention, distinguished compounds are those of Formula I in which :
    • A11 - A14 is CR11, CR12, CR13, CR14;
    • R1 is ethyl, cyclopropylmethyl, cyclopropylamino;
    • R2 and R3 are independently H or methyl;
    • R4 is H;
    • R5 is H, methyl, ethyl, propyl, isopropyl, butyl or benzyl;
    • the sulfonyl group with R1 is represented by R8 ;
    • the remaining R6-R14 are independently H or methyl;
    • R15 is CF3;
    • and R16 is methyl, CHF2, CF3, ethyl, 2,2-dimethylpropyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopentyl, phenyl or benzyl.
  • According to the present invention, distinguished compounds are those of Formula I in which :
    • A11 or A14 is N, the remaining position A being CR11 or CR14;
    • A12 and A13 are respectively CR12 and CR13 ;
    • R1 is C(3-6)cycloalkylC(1-3)alkyl;
    • R2 and R3 are independently H;
    • R4 is H;
    • R5 is H;
    • the sulfonyl group with R1 is represented by R8 ;
    • the remaining R6-R14 are independently H or methyl;
    • R15 and R16 are C(1-6)alkyl, with all carbon atoms of alkyl groups optionally substituted with one or more F.
  • According to the present invention, distinguished compounds are those of Formula I in which :
    • A11 or A14 is N, the remaining position A being CR11 or CR14;
    • A12 and A13 are respectively CR12 and CR13 ;
    • R1 is ethyl, cyclopropylmethyl, cyclopropylamino;
    • R2 and R3 are independently H or methyl;
    • R4 is H;
    • R5 is H, methyl, ethyl, propyl, isopropyl, butyl or benzyl;
    • the sulfonyl group with R1 is represented by R8 ;
    • the remaining R6-R14 are independently H or methyl;
    • R15 is methyl or CF3;
    • and R16 is methyl, CHF2, CF3, ethyl, 2,2-dimethylpropyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopentyl, phenyl or benzyl.
  • The invention also relates to a compound according to Formula I wherein R, is C(1-4)alkyl, C(3-5)cycloalkylC(1-3)alkyl or (di)C(3-4)cycloalkylamino.
  • In one embodiment the invention also relates to a compound according to Formula I wherein R1 is C(2-4)alkyl or C(3-5)cycloalkylC(1-3)alkyl.
  • In one embodiment the invention also relates to a compound according to Formula I wherein R1 is (di)C(3-4)cycloalkylamino.
  • In one embodiment the invention relates to a compound according to Formula I wherein R1 is ethyl or cyclopropylmethyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R1 is ethyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R1 is cyclopropylamino.
  • In one embodiment the invention relates to a compound according to Formula I wherein R1 is cyclopropylmethyl.
  • The invention also relates to a compound according to Formula I wherein R2 and R3 independently are H or methyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R2 and R3 independently are H.
  • The invention also relates to a compound according to Formula I wherein R4 is H.
  • The invention also relates to a compound according to Formula I wherein R5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)arylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano;
  • In one embodiment, R5 in Formula I is H, C(1-6)alkyl or C(6-10)arylC(1-3)alkyl.
  • In one embodiment, R5 in Formula I is H, methyl, ethyl, propyl, isopropyl, butyl or benzyl.
  • In one embodiment R5 in Formula I is H.
  • In one embodiment, R5 in Formula I is C(1-6)alkyl.
  • In one embodiment R5 in Formula I is C(6-10)arylC(1-3)alkyl.
  • The invention also relates to a compound according to Formula I wherein one of the groups R7, R8, Rg is the sulfonyl group with R1 attached to it and the others including R6 and R10 are independently H or C(1-6)alkyl.
  • In one embodiment the sulfonyl group is represented by R8, i.e. the sulfonyl group is attached at the para position of the aryl ring.
  • The invention also relates to a compound according to Formula I wherein R11-R14 are independently H, halogen, methyl or methoxy.
  • In one embodiment the invention relates to a compound according to Formula I wherein R11-R14 are independently H or methyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein A11-A14 are carbon atoms.
  • In one embodiment the invention relates to a compound according to Formula I-wherein A11 or A14 is nitrogen, the remaining position A is CR11 or CR14.
  • The invention also relates to a compound according to Formula I wherein
  • R15 is C(1)alkyl substituted with one or more F or R15 is C(2-6)alkyl optionally substituted with one or more F;
    and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F.
  • In one embodiment the invention relates to a compound according to Formule I wherein
    R15 is C(1)alkyl substituted with one or more F or R15 is C(2-6)alkyl optionally substituted with one or more F;
    and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(6-10)aryl or C(6-10)arylC(1-3)alkyl, all groups optionally substituted with one or more F.
  • In one embodiment the invention relates to a compound according to Formule I wherein R15 is CF3;
    and R16 is methyl, CHF2, CF3, ethyl, 2,2-dimethylpropyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopentyl, phenyl or benzyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein both R15 and R16 is CF3.
  • In one embodiment the invention relates to a compound according to Formula I wherein either R15 or R16 is CF3.
  • In one embodiment the invention relates to a compound according to Formula I wherein R15 is CF3 and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(6-10)aryl or C(6-10)arylC(1-3)alkyl, all groups optionally substituted with one or more F.
  • In one embodiment the invention relates to a compound according to Formula I wherein R15 is CF3 and R16 is methyl, CHF2, CF3, ethyl, 2,2-dimethylpropyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopentyl, phenyl or benzyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R15 is CF3 and R16 is C(1-6)alkyl, with all carbon atoms of the alkyl group optionally substituted with one or more F.
  • In one embodiment the invention relates to a compound according to Formula I wherein R15 is CF3 and R16 is methyl, CHF2, CF3, ethyl, 2,2-dimethylpropyl, propyl, isopropyl, butyl, isobutyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R15 is CF3 and R16 is C(3-6)cycloalkyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R15 is CF3 and R16 is cyclopropyl or cyclopentyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R15 is CF3 and R16 is C(6-10)aryl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R15 is CF3 and R16 is phenyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R15 is CF3 and R16 is or C(6-10)arylC(1-3)alkyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R15 is CF3 and R16 is benzyl.
  • The invention also relates to a compound according to Formula I wherein R5 is H and R15 is CF3 and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(6-10)aryl or C(6-10)arylC(1-3)alkyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R5 is H, R15 is CF3 and R16 is C(1-6)alkyl, with all carbon atoms of the alkyl group optionally substituted with one or more F.
  • In one embodiment the invention relates to a compound according to Formula I wherein R5 is H, R15 is CF3 and R16 is methyl, CHF2, CF3, ethyl, 2,2-dimethylpropyl, propyl, isopropyl, butyl, isobutyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R5 is H and both R15 and R16 are CF3.
  • In one embodiment the invention relates to a compound according to Formula I wherein R5 is H, R15 is CF3 and R16 is C(6-10)aryl, phenyl being the most preferred.
  • In one embodiment the invention relates to a compound according to Formula I wherein R5 is H, R15 is CF3 and R16 is C(3-6)cycloalkyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R5 is H, R15 is CF3 and R16 is cyclopropyl or cyclopentyl.
  • In one embodiment the invention relates to a compound according to Formula I wherein R5 is H, R15 is CF3 and R16 is C(6-10)arylC(1-3)alkyl.
  • In one embodiment the invention relates to a compound according to Formula I R5 is H, R15 is CF3 and R16 is benzyl.
  • The invention also relates to those compounds wherein all specific definitions for A11 through A14, R1 through R16, and all substituent groups in the various aspects of the inventions defined here above occur in any combination within the definition of the compound of Formula I.
  • In another aspect the invention relates to compounds of Formula I which have a pIC50 of 5 or higher. In yet another aspect the invention relates to compounds according to Formula I with a pIC50 of more than 6. In yet another aspect the invention relates to compounds according to Formula I with a pIC50 of more than 7.
  • In yet another aspect the invention resides in the compounds according to Formula I selected as described in examples 1 - 35.
  • Among the compounds according to the invention, mention may be made especially of the compounds below:
    N° Structure IUPAC name
    1
    Figure imgb0002
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)propyl]benzamide
    2
    Figure imgb0003
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)benzamide
    3
    Figure imgb0004
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(1-hydroxy-1-methyl-ethyl)benzamide
    4
    Figure imgb0005
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide
    5
    Figure imgb0006
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]benzamide
    6
    Figure imgb0007
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)butyl]benzamide
    7
    Figure imgb0008
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)pentyl]benzamide
    8
    Figure imgb0009
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-3-methyl-1-(trifluoromethyl)butyl]benzamide
    9
    Figure imgb0010
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzamide
    10
    Figure imgb0011
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-2-methyl-1-(trifluoromethyl)propyl]benzamide
    11
    Figure imgb0012
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(1-cyclopropyl-2,2,2-trifluoro-1-hydroxyethyl)benzamide
    12
    Figure imgb0013
         		4-(1-cyclopentyl-2,2,2-trifluoro-1-hydroxy-ethyl)-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]benzami de
    13
    Figure imgb0014
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(2,2,2-trifluoro-1-hydroxy-1-phenyl-ethyl)benzamide
    14
    Figure imgb0015
         		4-(1-benzyl-2,2,2-trifluoro-1-hydroxy-ethyl)-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]benzami de
    15
    Figure imgb0016
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-3-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide
    16
    Figure imgb0017
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]pyridine-2-carboxamide
    17
    Figure imgb0018
         		N-[(4-ethylsulfonylphenyl)methyl]-4-[1-hydroxy-1-(trifluoromethyl)propyl]benzamide
    18
    Figure imgb0019
         		N-[(4-ethylsulfonylphenyl)methyl]-4-[1-hydroxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzamide
    19
    Figure imgb0020
         		N-[(4-ethylsulfonylphenyl)methyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide
    20
    Figure imgb0021
         		N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)pentyl]benzamide
    21
    Figure imgb0022
         		N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide
    22
    Figure imgb0023
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]benzamide
    23
    Figure imgb0024
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzamide
    24
    Figure imgb0025
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-propoxy-1-(trifluoromethyl)ethyl]benzamide
    25
    Figure imgb0026
         		4-[1-butoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]benzami de
    26
    Figure imgb0027
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-isopropoxy-1-(trifluoromethyl)ethyl]benzamide
    27
    Figure imgb0028
         		4-[1-benzyloxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]benzami de
    28
    Figure imgb0029
         		N-[[4-(cyclopropylmethylsulfonyl)-2-methyl-phenyl]methyl]-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]benzamide
    29
    Figure imgb0030
         		N-[[4-(cyclopropylmethylsulfonyl)-2-methyl-phenyl]methyl]-4-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzamide
    30
    Figure imgb0031
         		N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]benzamide
    31
    Figure imgb0032
         		N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzamide
    32
    Figure imgb0033
         		N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-propoxy-1-(trifluoromethyl)ethyl]benzamide
    33
    Figure imgb0034
         		N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-methoxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzamide
    34
    Figure imgb0035
         		N-[(1R)-1-[4-(cyclopropylmethylsulfonyl)phenyl]ethyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide
    35
    Figure imgb0036
         		N-[(1S)-1-[4-(cyclopropylmethylsulfonyl)phenyl]ethyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide
  • The compounds of Formula I can form salts, which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • The compounds of Formula I may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula I as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g. hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of chiral HPLC column.
  • The skilled artisan will recognize that desirable IC50 values are dependent on the compound tested. For example, a compound with an IC50 value less than 10-5 M is generally considered a candidate for drug selection. Preferably, this value is lower than 10-6 M. However, a compound which has a higher IC50 value, but is selective for the particular receptor, may be even a better candidate.
  • The compounds of the invention inhibit RORγ activity. Modulation of RORγ activity can be measured using for example biophysical (natural) ligand displacement studies, biochemical AlphaScreen or FRET assays, cellular GAL4 reporter gene assays, cellular IL-17 promotor reporter assay or functional IL-17 ELISA assays using for example mouse splenocytes or human peripheral blood mononuclear cells (PBMCs) cultured under TH17 polarizing conditions.
  • In such assays, the interaction of a ligand with RORγ can be determined by measuring, for example, the ligand modulated interaction of cofactor-derived peptides with the RORγ ligand binding domain, or measuring the gene products of ligand modulated RORγ mediated transcription using, for example, luciferase reporter assays or IL-17 ELISA assays.
  • The present invention also relates to a pharmaceutical composition comprising compounds or pharmaceutically acceptable salts thereof having the general Formula I in admixture with pharmaceutically acceptable excipients and optionally other therapeutic agents. The excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • The invention further includes a compound of Formula I in combination with one or more other drug(s).
  • Compositions include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, topical, nasal, local or rectal administration, and the like, all in unit dosage forms for administration.
  • For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like.
  • For parenteral administration, the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use.
  • Mixed with such pharmaceutically acceptable excipients, the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically acceptable liquids the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
  • For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharma-ceutically acceptable additive which does not interfere with the function of the active compounds can be used. Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.
  • The invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.
  • The exact dose and regimen of administration of the active ingredient, or a pharmaceutical composition thereof, may vary with the particular compound, the route of administration, and the age and condition of the individual subject to whom the medicament is to be administered.
  • In general parenteral administration requires lower dosages than other methods of administration which are more dependent upon absorption. However, a dosage for humans preferably contains 0.0001-100 mg per kg body weight. The desired dose may be presented as one dose or as multiple sub-doses administered at appropriate intervals throughout the day.
  • The compounds according to the invention can be used in therapy.
  • A further aspect of the invention resides in the use of compounds according to the invention or a pharmaceutically acceptable salt thereof for the treatment of RORγ-mediated diseases or RORγ mediated conditions.
  • The compounds according to the invention can be used in as medicament.
  • Another aspect of the invention resides in the use of compounds having the general Formula I or a pharmaceutically acceptable salt thereof for the treatment of autoimmune diseases, in particular those diseases in which Th17 cells and non-Th17 cells, which express Th17 hallmark cytokines play a prominent role. These include, but are not limited to, the treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn's disease and multiple sclerosis.
  • In another aspect, compounds having the general Formula I or a pharmaceutically acceptable salt thereof can be used for treatment of inflammatory diseases in which Th17 cells and/or non-Th17 cells, which express Th17 hallmark cytokines play a prominent role such as, but not limited to respiratory diseases, osteoarthritis and asthma. Also, compounds or a pharmaceutically acceptable salt thereof having the general Formula I can be used for treatment of infectious diseases in which Th17 cells and/or non-Th17 cells, which express Th17 hallmark cytokines play a prominent role such as, but not limited to mucosal leishmaniasis.
  • Compounds having the general Formula I or a pharmaceutically acceptable salt thereof can also be used for treatment of other diseases in which Th17 cells and/or non-Th17 cells, which express Th17 hallmark cytokines play a prominent role such as, but not limited to Kawaski disease and Hashimoto's thyroiditis.
  • In yet another aspect the invention resides in the use of compounds having the general Formula I for the treatment of multiple sclerosis, inflammatory bowel disease, Crohn's disease, psoriasis, rheumatoid arthritis, asthma, osteoarthritis, Kawaski disease, Hashimoto's thyroiditis, cancer and mucosal leishmaniasis.
  • In another aspect, the compounds according to the invention can be used in therapies to treat or prevent multiple sclerosis, inflammatory bowel disease, Crohn's disease, psoriasis and rheumatoid arthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, cancer and mucosal leishmaniasis.
  • In another aspect the compounds according to the invention can be used to treat or prevent psoriasis.
  • In yet another aspect the compounds according to the invention can be used to treat inflammatory bowel disease.
  • The invention is illustrated by the following examples.
    • EXEMPLIFICATION
  • As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the invention, the following general methods, and other methods known to one skilled in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
    • GENERAL METHODS OF PREPARATION.
  • The compounds described herein, including compounds of general Formula I, building blocks II, III, IV and V can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. Many of the reactions can also be carried out under microwave conditions or using conventional heating or utilizing other technologies such as solid phase reagents/scavengers or flow chemistry. For example, hydrogenation reactions can be performed using a continuous flow chemistry apparatus such as the H-Cube Pro® from ThalesNano Nanotechnology company in Budapest, Hungary. In these reactions, it is also possible to make use of variants which are themselves known to those skilled in the art, but are not mentioned in greater detail. For example, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents, solvents etc. may be used and are included within the scope of the present invention. Furthermore, other methods for preparing compounds of the invention will be readily apparent to a person of ordinary skill in the art in light of the following reaction schemes and examples. In cases where synthetic intermediates and final products contain potentially reactive functional groups, for example amino, hydroxyl, thiol and carboxylic acid groups that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. The compounds obtained by using the general reaction sequences may be of insufficient purity. The compounds can be purified by using any of the methods of purification of organic compounds, for example, crystallization or silica gel or alumina column chromatography, using different solvents in suitable ratios. All possible stereoisomers are envisioned within the scope of the invention. In the discussion below variables have the meaning indicated above unless otherwise indicated.
  • The abbreviations used in these experimental details are listed below and additional ones should be considered known to a person skilled in the art of synthetic chemistry.
  • Abbreviations used herein are as follow: HATU: 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; DMF: Dimethylformamide; DiPEA: Diisopropylethylamine; DMAP: 4-(dimethylamino)pyridine; CH2Cl2, DCM: dichloromethane; DCC: N,N'-Dicyclohexylcarbodiimide; mCPBA: 3-chloroperoxybenzoic acid; TFA: Trifluoroacetic acid; TFAA: Trifluoroacetic anhydride; THF: Tetrahydrofuran; cont.: continuous; DMSO: Dimethylsulfoxide; PTSA: p-Toluenesulfonic acid; PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; EtOH: Ethanol; DIAD: Diisopropyl azodicarboxylate; TLC: Thin Layer Chromatography; Pd(dba)2: Bis(dibenzylideneacetone)palladium(0); PPh3: Triphenyl phosphine; NMP: N-Methyl-2-pyrrolidinone; EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; BuLi: n-Butyl lithium; TBAF: Tetra-N-butylammonium fluoride; TMS: Trimethylsilyl; EtOAc: ethyl acetate; ACN, CH3CN: acetonitrile; RT: room temperature; MeOH: methanol; Et3N, TEA: triethylamine, K2CO3 : potassium carbonate, MgSO4: magnesium sulfate; NaOH: sodium hydroxide, NaHCO3: sodium bicarbonate; Na2SO3: sodium sulfite; TMSCF3: Trifluoromethyltrimethylsilane; H2O: water; HCl: hydrochloric acid.
  • Chemical names are preferred IUPAC names, generated using Accelrys Draw 4.1.
  • If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates.
    • GENERAL PROCEDURES
  • Figure imgb0037
    • Conditions: i) EDCI, DMAP, CH2Cl2.
  • As depicted in scheme 1, the derivatives of the invention having Formula I can be prepared by methods known in the art of organic chemistry. Compounds of the invention can for example be obtained by an amide coupling reaction between an amine derivative of building block II, wherein R1, R2, R3, R4, R6, R7, R8, Rg and R10 are as defined for compound Formula I and a carboxylic acid derivative of building block III (X1 is OH), wherein R5, R15, R16, A11, A12, A13 and A14 are as defined for compound of Formula I, using a coupling reagent such as EDCI, HATU, DCC, or PyBOP or the like, in the presence of a suitable base such as DiPEA or DMAP.
  • Alternatively, the carboxylic acid derivative of building block III (X1 = OH) can be converted into an acyl chloride derivative of building block III (X1 = Cl), using for example SOCl2 or oxalyl chloride. The obtained acyl chloride derivative of building block III (X1 = CI), wherein R5, R15, R16, A11, A12, A13 and A14 are as defined for compounds of Formula I, can be coupled with an amine derivative of building block II, wherein R1, R2, R3, R4, R6, R7, R8, R9 and R10 have the meaning as previously described in the presence of a suitable base such as Et3N or the like.
    Figure imgb0038
    • Conditions: i) CuOSO2CF3, 1,2-diaminocyclohexane, DMSO, 125°C.
  • Scheme 2 demonstrates an alternative route for the preparation of derivatives of Formula I wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, F10, R15, R16, A11, A12, A13 and A14 are as defined for compounds of Formula I.
  • Compounds of the invention can be obtained for example by a coupling of an aryl bromide (X2 = Br) or iodide (X2 = I) derivative of building block IV and a sulfinic acid salt derivative of building block V such as a sodium sulfinate, using a copper(I) catalyst such as copper(I) trifluoromethanesulfonate benzene complex, copper(I) iodide or the like, in the presence of a suitable ligand such as trans-1,2-diaminocyclohexane, phenanthroline, dimethylimidazolidinone, or the like. The reaction is performed by heating the mixture in a polar solvent such as DMSO, DMF or the like at temperature between 80 and 140°C using microwave or conventional heating conditions.
    Figure imgb0039
    • Conditions: i) Na2SO3, NaHCO3, water, 70°C; ii) alkylhalide, anhydrous DMSO, 100°C; iii) K2CO3, alkylhalide, CH3CN, RT; iv) mCPBA, DCM, 0°C -> RT; v) H2, Raney Ni, NH3 / MeOH, 70 °C.
  • Scheme 3 illustrates general methods for the preparation of building blocks II wherein R1, R6, R7, Rg and R10 are as defined for compounds of Formula I.
  • 4-Cyanobenzenesulfonyl chloride derivatives 1 on reaction with sodium sulfite in the presence of a suitable base such as sodium bicarbonate give the corresponding sulfinate derivatives 2 , which can be alkylated with an appropriate alkylhalide to give alkylsulfonylbenzonitrile derivatives 5.
  • Alternatively, 4-mercapto-2-methylbenzonitrile derivatives 3 can be alkylated in the presence of a suitable base such as potassium carbonate to give the corresponding thioether derivatives 4 . Oxidation, using e. g. mCPBA, gives alkylsulfonylbenzonitrile derivatives 5 , which after hydrogenation of the nitrile moiety using a suitable catalyst such as Raney nickel gives benzylamines of Formula II.
    Figure imgb0040
    • Conditions: i) a suitable primary or secondary amine, Et3N, DCM, RT; ii) H2, Raney Ni, NH3 / MeOH, cont. flow, 70°C.
  • Scheme 4 illustrates a general reaction scheme for the preparation of building blocks II wherein R1 is (di)C(3-6)cycloalkylamino or (di)(C(3-6)cycloalkylC(1-3)alkyl)amino as previously described and R6, R7, Rg and R10 are as defined for compounds of Formula I. 4-Cyanobenzenesulfonyl chloride derivatives 1 on reaction with primary or secondary amines in the presence of a suitable base such as TEA give the corresponding sulfonamide derivatives 6 , which can be hydrogenated using a suitable catalyst such as Raney nickel to obtain benzylamines of Formula II wherein R1 is (di)C(3-6)cycloalkylamino or (di)(C(3-6)cycloalkylC(1-3)alkyl)amino as previously described.
  • Some of the building blocks II used in the examples of general Formula I are commercially available, known or prepared according to methods known to those skilled in the art.
    Figure imgb0041
    • Conditions: (R 15 = CF 3 ) i) TMSCF3, TBAF, THF; ii) NaOH, THF, EtOH; iii) suitable alkyl halide, base, solvent.
  • Scheme 5 illustrates a general reaction scheme for the preparation of building blocks III wherein R15 is CF3 and R5, R16, A11, A12, A13 and A14 are as defined for compounds of Formula I.
  • Ketone derivatives 7 wherein R is H or lower alkyl such as methyl or ethyl can be treated with TMSCF3 and TBAF to give the corresponding alcohol derivatives 8 , which can be hydrolyzed by a hydroxide source such as NaOH to obtain building blocks III wherein R15 is CF3, R5 is H and R16, A11, A12, A13 and A14 are as previously described. In the case where R is H, the hydrolysis step is not needed since the alcohol derivatives 8 wherein R is H correspond to building blocks III wherein R15 is CF3 and R5 is H.
  • Alcohol derivatives 8 can be alkylated with a suitable alkyl halide in presence of a base such as potassium carbonate, sodium hydride or the like to give ether derivatives 9 which can then be hydrolyzed to building blocks III wherein R15 is CF3 and R5, R16, A11, A12, A13 and A14 with the proviso that R5 is not H. In certain cases, when commercially available, alcohol derivatives 8 wherein R is H can be dialkylated with 2 equivalents of a suitable alkyl halide in presence of a base to give ether derivatives 9 wherein R = R5 which can then be hydrolyzed to building blocks III wherein R15 is CF3 and R5 is not H. Some of the building blocks III used in the examples of general Formula I are commercially available, known or prepared according to methods known to those skilled in the art.
    Figure imgb0042
    • Conditions: i) EDCI, DMAP, CH2Cl2.
  • As depicted in scheme 6, the building blocks IV can be prepared by an amide coupling reaction between an amine derivative 10, wherein R2, R3, R4, R6, R7, R8, R9, R10 are as previously described and X2 is Br or I and a carboxylic acid derivative of building block III, wherein R5, R15, R16, A11, A12, A13 and A14 are as defined for compounds of Formula I, using a coupling reagent such as EDCI, HATU, DCC, or PyBOP or the like, in the presence of a suitable base such as DiPEA or DMAP.
    Figure imgb0043
    • Conditions: i) Na2SO3, NaHCO3, H2O, 50 °C.
  • Scheme 7 shows a general reaction scheme for the preparation of building blocks V wherein R1 has the meaning as previously described.
  • Sulfonyl chlorides 11 can be converted to sodium sulfinate derivatives of building block V by treatment with sodium sulfite in water in the presence of a suitable base such as sodium bicarbonate.
  • Some of the building blocks V are commercially available, known or prepared according to methods known to those skilled in the art.
    • Intermediates Building blocks II-1 - III-3 II-1: [4-(cyclopropylmethylsulfonyl)phenyl]methanamine.
  • Figure imgb0044
    • i) To a solution of 4-cyanobenzenesulfonyl chloride (75 g) in water (281 mL) was added portionwise NaHCO3 (62.5 g) followed by sodium sulfite (93.8 g). The reaction mixture was stirred for 3 hours at 70°C, then cooled to RT and concentrated under reduced pressure. MeOH (500 mL) was added and the mixture was concentrated to a small volume, then filtered. The solid was taken into MeOH (500 mL), mechanically stirred then filtered. The combined filtrates were taken into EtOAc and concentrated under high vacuum to obtain 71 g of sodium 4-cyanobenzenesulfinate. MS(ES-) m/z 166 [M-H]-.
    • ii) A solution of the compound obtained in the preceding step (5g) in anhydrous dimethyl sulfoxide (50 mL) and bromomethylcyclopropane (2.6 mL) was stirred for 1 hour and 45 minutes at 100°C in an autoclave. Bromomethylcyclopropane (2.6 mL) was then added and the mixture was stirred another hour at 100°C. After being cooled to RT, the reaction mixture was poured into water (150 mL) and extracted with EtOAc (3x50 mL). The combined extracts were washed with brine (4x100 mL), dried over MgSO4 and concentrated under reduced pressure to obtain 3.8 g of 4-(cyclopropylmethylsulfonyl)benzonitrile. MS(ES+) m/z 222 [M+H]+.
    • iii) A solution of the compound obtained in the preceding step (1.7 g) in 2N ammonia in MeOH (250 mL) was passed through the continuous flow hydrogenation apparatus H-Cube Pro® equipped with a fresh Raney Nickel cartridge (70 X 4mm i.d.) using the settings: flow rate 1 mL/min, H2 pressure 50 bars and cartridge temperature (70°C). The reaction mixture was then evaporated and purified by column chromatography on silica gel, using 0% to 18% MeOH in EtOAc as the eluent to obtain 1.6 g of expected product. MS(ES+) m/z 226.0 [M+H]+.
    II-2: [4-(cyclopropylmethylsulfonyl)-2-methyl-phenyl]methanamine.
  • Figure imgb0045
    • i) To a solution of 2-methyl-4-sulfanyl-benzonitrile (3.0 g) in ACN (55 mL) under argon were added K2CO3 (7.0 g) followed by bromomethylcyclopropane (2.3 mL). The reaction mixture was stirred at RT overnight, filtered and then concentrated under reduced pressure to obtain 4.06 g of 4-(cyclopropylmethylsulfanyl)-2-methyl-benzonitrile. MS(ES+) m/z 204 [M+H]+.
    • ii) To a solution of the compound obtained in the preceding step (4.06 g) in DCM (180 mL) precooled to 0°C was added portionwise mCPBA (13.4 g). The reaction mixture was then stirred at RT for one hour, washed with an aqueous solution saturated with NaHCO3, then with water and finally with brine. The extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 0% to 20% EtOAc in heptane as the eluent to obtain 3.93 g of 4-(cyclopropylmethylsulfonyl)-2-methyl-benzonitrile. MS(ES+) m/z 236 [M+H]+.
    • iii) A solution of 1.0 g of the compound obtained in the preceding step in 2N ammonia in MeOH (80 mL) and Raney Nickel (24.9 mg) was stirred under a stream of H2 (50 bars) in an autoclave during 4 hours at 70 °C. After being cooled to RT, the reaction mixture was filtered over celite and concentrated under reduced pressure to obtain 1.03 g of the expected product. MS(ES+) m/z 240.1 [M+H]+.
    II-3: 4-(aminomethyl)-N-cyclopropyl-benzenesulfonamide.
  • Figure imgb0046
    • i) Cyclopropanamine (0.4 mL) and then TEA (1.5 mL) were added to a solution of 4-cyanobenzenesulfonyl chloride (1.0 g) in DCM (10 mL). The reaction was exothermic, and temperature was kept below 35°C. After stirring overnight at RT, the reaction mixture was poured into water (15 mL) and extracted with DCM (2x20 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4 filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, using DCM as the eluent to obtain 449 mg of 4-cyano-N-cyclopropyl-benzenesulfonamide. MS(ES-) m/z 221 [M-H]-.
    • ii) A solution of the compound obtained in the preceding step (449 mg) in 2N ammonia in MeOH (250 mL) was passed through the continuous flow hydrogenation apparatus H-Cube Pro® equipped with a fresh Raney Nickel cartridge (70 X 4mm i.d.) using the settings: flow rate 1 mL/min, H2 pressure 50 bars and cartridge temperature (70°C). The reaction mixture was then evaporated and purified by column chromatography on silica gel, using 0% to 18% MeOH in EtOAc as the eluent to obtain 367 mg of expected product. MS(ES+) m/z 226.0 [M+H]+.
    Building blocks III-1 - III-14 III-1: 4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)benzoic acid.
  • Figure imgb0047
    • i) To a solution of methyl 4-acetylbenzoate (1g) in anhydrous THF (10 mL) was added TMSCF3 (2.5 mL) followed by dropwise addition of a 1 M solution of TBAF in THF (15.7 mL). The reaction mixture was stirred for 18 hours at RT then taken into ether (50 mL), washed with water (50 mL) and brine (50 mL), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, using 0% to 30% EtOAc in cyclohexane as the eluent to obtain 750 mg of methyl 4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)benzoate. MS(ES+) m/z 249.0 [M+H]+.
    • ii) To a solution of the compound obtained in the preceding step (600 mg) in THF (10 mL) was added a 1 N aqueous solution of NaOH (3.6 mL). After stirring for 18 hours at RT, the reaction was not complete. Additional 1 N aqueous solution of NaOH (1.2 mL,) was added. The reaction mixture was stirred for an additional 5 hours at RT then taken into ether (40 mL) and water (20 mL). The aqueous layer was separated, acidified with a 1 N aqueous solution of HCl (2 equivalents), extracted twice with ether (50 mL), dried over MgSO4 and concentrated under reduced pressure to obtain 550 mg of the expected compound. MS(ES-) m/z 233.0 [M-H]-.
  • Following a procedure analogous to that described for compound III-1, the following compounds were prepared.
    • III-2: 4-[1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]benzoic acid.
  • Figure imgb0048
     MS(ES-) m/z 269.0 [M-H]-.
    • III-3: 4-[1-hydroxy-1-(trifluoromethyl)propyl]benzoic acid.
  • Figure imgb0049
     MS(ES-) m/z 247.0 [M-H]-.
    • III-4: 4-[1-hydroxy-1-(trifluoromethyl)butyl]benzoic acid.
  • Figure imgb0050
     MS(ES-) m/z 261.0 [M-H]-.
    • III-5: 4-[1-hydroxy-1-(trifluoromethyl)pentyl]benzoic acid.
  • Figure imgb0051
     MS(ES-) m/z 275.1 [M-H]-.
    • III-6: 4-[1-hydroxy-3-methyl-1-(trifluoromethyl)butyl]benzoic acid.
  • Figure imgb0052
     MS(ES-) m/z 275.0 [M-H]-.
    • III-7: 4-[1-hydroxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzoic acid.
  • Figure imgb0053
     MS(ES-) m/z 289.0 [M-H]-.
    • III-8: 4-[1-hydroxy-2-methyl-1-(trifluoromethyl)propyl]benzoic acid.
  • Figure imgb0054
     MS(ES-) m/z 261.0 [M-H]-.
    • III-9: 4-(1-cyclopropyl-2,2,2-trifluoro-1-hydroxy-ethyl)benzoic acid.
  • Figure imgb0055
     MS(ES-) m/z 259.0 [M-H]-.
    • III-10: 4-(1-cyclopentyl-2,2,2-trifluoro-1-hydroxy-ethyl)benzoic acid.
  • Figure imgb0056
     MS(ES-) m/z 287.0 [M-H]-.
    • III-11: 4-(2,2,2-trifluoro-1-hydroxy-1-phenyl-ethyl)benzoic acid.
  • Figure imgb0057
     MS(ES-) m/z 295.0 [M-H]-.
    • III-12: 4-(1-benzyl-2,2,2-trifluoro-1-hydroxy-ethyl)benzoic acid.
  • Figure imgb0058
     MS(ES+) m/z 311.0 [M+H]+.
    • III-13: 3-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzoic acid.
  • Figure imgb0059
     MS(ES-) m/z 301.1 [M-H]-.
    • III-14: 5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]pyridine-2-carboxylic acid.
  • Figure imgb0060
     MS(ES-) m/z 287.9 [M-H]-.
    • Building blocks III-15 - III-21 III-15: 4-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzoic acid.
  • Figure imgb0061
    • i) To a solution of 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzoic acid (500 mg) in acetone (10 mL) were added K2CO3 (959.27 mg) followed by iodoethane (1.08 g). The reaction mixture was stirred overnight at RT, then heated to 60°C for 5 hours, concentrated under reduced pressure and taken into DCM/water. The extract was separated and concentrated under reduced pressure to obtain 510 mg of ethyl 4-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzoate. MS(ES+) m/z 345 [M+H]+.
    • ii) To a solution of the compound obtained in the preceding step (510 mg) in THF (3 mL) and ethanol (3 mL) was added a 2M aqueous solution of NaOH (1.48 mL). The reaction mixture was stirred for 1 hour at RT then poured into a 2M aqueous solution of HCl (3.1 mL) and extracted with EtOAc. The extract was washed with brine and concentrated under reduced pressure to obtain 430 mg of the expected compound. MS(ES-) m/z 315.0 [M-H]-.
  • Following a procedure analogous to that described for compound III-15, the following compounds were prepared.
    • III-16: 4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]benzoic acid.
  • Figure imgb0062
     MS(ES-) m/z 300.9 [M-H]-.
    • III-17: 4-[2,2,2-trifluoro-1-propoxy-1-(trifluoromethyl)ethyl]benzoic acid.
  • Figure imgb0063
     MS(ES-) m/z 329.0 [M-H]-.
    • III-18: 4-[1-butoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzoic acid.
  • Figure imgb0064
     MS(ES-) m/z 343.0 [M-H]-.
    • III-19: 4-[2,2,2-trifluoro-1-isopropoxy-1-(trifluoromethyl)ethyl]benzoic acid.
  • Figure imgb0065
     MS(ES-) m/z 329.0 [M-H]-.
    • III-20: 4-[1-benzyloxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzoic acid.
  • Figure imgb0066
     MS(ES-) m/z 377.0 [M-H]-.
    • III-21: 4-[1-methoxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzoic acid.
  • Figure imgb0067
     MS(ES+) m/z 305.2 [M+H]+.
    • Building blocks IV-1 - IV-2 IV-1: N-[(1 R)-1-(4-bromophenyl)ethyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0068
    • i) To a solution of (1R)-1-(4-bromophenyl)ethanamine (694 mg) in DCM (25 mL) was added 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzoic acid (1 g), EDCl (679 mg) and DMAP (85 mg). The reaction mixture was stirred at RT for 30 minutes. DCM and water were added. The mixture was filtered on water repellent filter cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 20% EtOAc in heptane as the eluent, to obtain 950 mg of the expected compound. MS(ES+) m/z 470 [M+H]+.
  • Following a procedure analogous to that described for compound IV-1, the following compound was prepared.
    • IV-2: N-[(1S)-1-(4-bromophenyl)ethyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0069
     MS(ES+) m/z 469.9 [M+H]+.
    • Building blocks V-1 V-1: Sodium cyclopropylmethanesulfinate.
  • Figure imgb0070
    • i) A solution of Na2SO3 (414 mg) in water (1.3 mL) was stirred for 10 minutes at RT. To the resulting mixture was added NaHCO3 (547 mg). After stirring for 1 hour at 50°C, cyclopropylmethanesulfonyl chloride (430 mg) was added dropwise. The reaction mixture was stirred at 50°C for 4 hours. Water was evaporated by flushing argon. The residue was dried under high vacuum. The residue was taken into MeOH (1.3 mL), filtered and concentrated under reduced pressure to obtain 380 mg of expected product. MS(ES+) m/z 120.9 [M+H]+.
    Examples 1 - 35: 1: N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)propyl]benzamide.
  • Figure imgb0071
    • i) To a solution of an amine II-1 (100 mg) in DCM (3 ml) were sequentially added acid III-2 (121 mg), EDCI (107.5 mg) and DMAP (11 mg). The mixture was stirred at RT for 2 hours. EtOAc (50 mL) and water (50 mL) were added. The aqueous layer was separated and extracted twice with EtOAc. The combined extracts were washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 0% to 60% EtOAc in cyclohexane as the eluent, to obtain 130 mg of expected product. MS(ES+) m/z 456.0 [M+H]+.
      1 H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (t, J=6.02 Hz, 1 H) 7.83 - 7.94 (m, 4 H) 7.65 (d, J=8.28 Hz, 2 H) 7.58 (d, J=8.28 Hz, 2 H) 6.49 (br s, 1 H) 4.59 (d, J=6.02 Hz, 2 H) 3.20 - 3.28 (m, 2 H) 2.23 (dq, J=14.21, 7.31 Hz, 1 H) 1.97 - 2.07 (m, 1 H) 0.77 - 0.87 (m, 1 H) 0.67 (t, J=7.40 Hz, 3 H) 0.41 - 0.47 (m, 2 H) 0.09 - 0.14 (m, 2 H)
  • Following a procedure analogous to that described for Example 1, using the appropriate building blocks II and III or any commercially available ones, the following compounds were prepared.
    • 2 : N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)benzamide.
  • Figure imgb0072
     MS(ES+) m/z 442.0 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (t, J=6.02 Hz, 1 H) 7.83 - 7.94 (m, 4 H) 7.70 (d, J=8.28 Hz, 2 H) 7.57 (d, J=8.28 Hz, 2 H) 6.70 (s, 1 H) 4.60 (d, J=5.77 Hz, 2 H) 3.19 - 3.25 (m, 2 H) 1.71 (s, 3 H) 0.77 - 0.87 (m, 1 H) 0.41 - 0.47 (m, 2 H) 0.08 - 0.14 (m, 2 H).
    • 3 : N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(1-hydroxy-1-methyl-ethyl)benzamide.
  • Figure imgb0073
     MS(ES+) m/z 388.2 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.06 (t, J=5.90 Hz, 1 H) 7.82 - 7.88 (m, 4 H) 7.56 (d, J=8.28 Hz, 4 H) 5.10 (s, 1 H) 4.58 (d, J=6.02 Hz, 2 H) 3.22 (d, J=7.03 Hz, 2 H) 1.44 (s, 6 H) 0.77 - 0.87 (m, 1 H) 0.41 - 0.47 (m, 2 H) 0.09 - 0.14 (m, 2 H).
    • 4: N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0074
     MS(ES+) m/z 496.2 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.2 (m, 1 H) 8.8 (s, 1 H) 7.9 (m, 2 H) 7.7 (m, 2 H) 7.6 (m, 2 H) 7.5 (m, 2 H) 4.5 (m, 2 H) 3.1 (m, 2 H) 0.7 (m, 1 H) 0.3 (m, 2 H) 0.0 (m, 2 H).
    • 5: N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]benzamide.
  • Figure imgb0075
     MS(ES+) m/z 478.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (t, J=5.90 Hz, 1 H) 7.98 (d, J=8.53 Hz, 2 H) 7.93 (br s, 1 H) 7.83 - 7.89 (m, 2 H) 7.77 (d, J=8.53 Hz, 2 H) 7.58 (d, J=8.53 Hz, 2 H) 6.58 - 6.97 (m, 1 H) 4.60 (d, J=6.02 Hz, 2 H) 3.20 - 3.28 (m, 2 H) 0.77 - 0.88 (m, 1 H) 0.38 - 0.48 (m, 2 H) 0.09 - 0.17 (m, 2 H).
    • 6 : N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)butyl]benzamide.
  • Figure imgb0076
     MS(ES+) m/z 470.1 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (t, J=5.90 Hz, 1 H) 7.83 - 7.93 (m, 4 H) 7.65 (d, J=8.53 Hz, 2 H) 7.57 (d, J=8.28 Hz, 2 H) 6.52 (s, 1 H) 4.59 (d, J=5.77 Hz, 2 H) 3.22 (d, J=7.28 Hz, 2 H) 2.13 - 2.22 (m, 1 H) 1.90 - 1.99 (m, 1 H) 1.26 - 1.38 (m, 1 H) 0.77 - 0.89 (m, 5 H) 0.41 - 0.46 (m, 2 H) 0.09 - 0.13 (m, 2 H).
    • 7 : N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)pentyl]benzamide.
  • Figure imgb0077
     MS(ES+) m/z 484.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (t, J=6.02 Hz, 1 H) 7.91 (d, J=8.53 Hz, 2 H) 7.85 (d, J=8.28 Hz, 2 H) 7.65 (d, J=8.28 Hz, 2 H) 7.58 (d, J=8.28 Hz, 2 H) 6.51 (br s, 1 H) 4.59 (d, J=6.02 Hz, 2 H) 3.22 (d, J=7.03 Hz, 2 H) 2.13 - 2.25 (m, 1 H) 1.90 - 2.03 (m, 1 H) 1.19 - 1.34 (m, 3 H) 0.75 - 0.85 (m, 5 H) 0.40 - 0.48 (m, 2 H) 0.08 - 0.15 (m, 2 H).
    • 8 : N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-3-methyl-1-(trifluoromethyl)butyl]benzamide.
  • Figure imgb0078
     MS(ES+) m/z 484.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (t, J=6.02 Hz, 1 H) 7.83 - 7.93 (m, 4 H) 7.67 (d, J=8.53 Hz, 2 H) 7.58 (d, J=8.53 Hz, 2 H) 6.51 (s, 1 H) 4.59 (d, J=6.02 Hz, 2 H) 3.18 - 3.28 (m, 2 H) 2.16 (dd, J=14.18, 5.65 Hz, 1 H) 1.86 (dd, J=14.31, 7.03 Hz, 1 H) 1.52 (dquin, J=13.05, 6.53, 6.53, 6.53, 6.53 Hz, 1 H) 0.76 - 0.89 (m, 4 H) 0.59 (d, J=6.53 Hz, 3 H) 0.40 - 0.48 (m, 2 H) 0.09 - 0.17 (m, 2 H).
    • 9 : N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzamide.
  • Figure imgb0079
     MS(ES+) m/z 498.2 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (t, J=6.02 Hz, 1 H) 7.83 - 7.92 (m, 4 H) 7.72 (d, J=8.28 Hz, 2 H) 7.58 (d, J=8.28 Hz, 2 H) 6.41 (s, 1 H) 4.59 (d, J=6.02 Hz, 2 H) 3.22 (d, J=7.03 Hz, 2 H) 2.24 (d, J=14.31 Hz, 1 H) 1.97 (d, J=14.56 Hz, 1 H) 0.77 - 0.89 (m, 1 H) 0.70 - 0.75 (m, 9 H) 0.41 - 0.47 (m, 2 H) 0.09 - 0.14 (m, 2 H).
    • 10: N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-2-methyl-1-(trifluoromethyl)propyl]benzamide.
  • Figure imgb0080
     MS(ES+) m/z 470.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (t, J=5.90 Hz, 1 H) 7.83 - 7.94 (m, 4 H) 7.56 - 7.67 (m, 4 H) 6.36 (br s, 1 H) 4.59 (d, J=6.02 Hz, 2 H) 3.20 - 3.25 (m, 2 H) 2.47 - 2.51 (m, 1 H) 1.07 (br d, J=6.27 Hz, 3 H) 0.77 - 0.88 (m, 1 H) 0.63 (d, J=6.78 Hz, 3 H) 0.40 - 0.48 (m, 2 H) 0.09 - 0.17 (m, 2 H).
    • 11 : N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(1-cyclopropyl-2,2,2-trifluoro-1-hydroxy-ethyl)benzamide.
  • Figure imgb0081
     MS(ES+) m/z 468.0 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (t, J=6.02 Hz, 1 H) 7.83 - 7.94 (m, 4 H) 7.74 (d, J=8.53 Hz, 2 H) 7.57 (d, J=8.28 Hz, 2 H) 6.19 (s, 1 H) 4.60 (d, J=6.02 Hz, 2 H) 3.22 (d, J=7.28 Hz, 2 H) 1.69 (tt, J=8.34, 5.21 Hz, 1 H) 0.75 - 0.87 (m, 2 H) 0.51 - 0.60 (m, 1 H) 0.41 - 0.48 (m, 2 H) 0.31 - 0.40 (m, 1 H) 0.20 - 0.30 (m, 1 H) 0.09 - 0.17 (m, 2 H).
    • 12: 4-(1-cyclopentyl-2,2,2-trifluoro-1-hydroxy-ethyl)-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]benzamide.
  • Figure imgb0082
     MS(ES+) m/z 496.2 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (t, J=6.00 Hz, 1 H) 7.91 (m, J=8.53 Hz, 2 H) 7.85 (m, J=8.28 Hz, 2 H) 7.67 (m, J=8.53 Hz, 2 H) 7.58 (m, J=8.28 Hz, 2 H) 6.34 (s, 1 H) 4.59 (d, J=6.02 Hz, 2 H) 3.22 (d, J=7.03 Hz, 2 H) 2.75 (quin, J=8.97 Hz, 1 H) 1.33 - 1.89 (m, 6 H) 1.04 - 1.27 (m, 2 H) 0.72 - 0.94 (m, 1 H) 0.41 - 0.46 (m, 2 H) 0.09 - 0.13 (m, 2 H).
    • 13: N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(2,2,2-trifluoro-1-hydroxy-1-phenyl-ethyl)benzamide.
  • Figure imgb0083
     MS(ES+) m/z 504.0 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (t, J=5.90 Hz, 1 H) 7.83 - 7.93 (m, 4 H) 7.34 - 7.58 (m, 10 H) 4.59 (d, J=6.02 Hz, 2 H) 3.19 - 3.28 (m, 2 H) 0.76 - 0.88 (m, 1 H) 0.41 - 0.46 (m, 2 H) 0.08 - 0.13 (m, 2 H).
    • 14: 4-(1-benzyl-2,2,2-trifluoro-1-hydroxy-ethyl)-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]benzamide.
  • Figure imgb0084
     MS(ES+) m/z 518.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (t, J=5.90 Hz, 1 H) 7.83 (t, J=8.53 Hz, 4 H) 7.63 (d, J=8.28 Hz, 2 H) 7.56 (d, J=8.53 Hz, 2 H) 7.03 - 7.14 (m, 5 H) 6.87 (s, 1 H) 4.56 (d, J=5.77 Hz, 2 H) 3.55 (d, J=14.05 Hz, 1 H) 3.31 - 3.39 (m, 1 H) 3.19 - 3.28 (m, 2 H) 0.76 - 0.86 (m, 1 H) 0.40 - 0.47 (m, 2 H) 0.08 - 0.15 (m, 2 H)
    • 15: N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-3-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0085
     MS(ES+) m/z 510.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.21 (t, J=5.90 Hz, 1 H) 8.67 (br s, 1 H) 7.76 - 7.87 (m, 4 H) 7.55 - 7.61 (m, 3 H) 4.59 (d, J=6.02 Hz, 2 H) 3.22 (d, J=7.03 Hz, 2 H) 2.64 (s, 3 H) 0.77 - 0.87 (m, 1 H) 0.40 - 0.48 (m, 2 H) 0.09 - 0.17 (m, 2 H).
    • 16: N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]pyridine-2-carboxamide.
  • Figure imgb0086
     MS(ES+) m/z 497.0 [M+H]+.
    • 17: N-[(4-ethylsulfonylphenyl)methyl]-4-[1-hydroxy-1-(trifluoromethyl)propyl]benzamide.
  • Figure imgb0087
     MS(ES+) m/z 430.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (t, J=5.90 Hz, 1 H) 7.92 (d, J=8.53 Hz, 2 H) 7.81 - 7.87 (m, 2 H) 7.65 (d, J=8.53 Hz, 2 H) 7.59 (d, J=8.53 Hz, 2 H) 6.49 (s, 1 H) 4.59 (d, J=6.02 Hz, 2 H) 3.25 (q, J=7.36 Hz, 2 H) 2.23 (dq, J=14.31, 7.36 Hz, 1 H) 1.97 - 2.08 (m, 1 H) 1.09 (t, J=7.28 Hz, 3 H) 0.67 (t, J=7.28 Hz, 3 H).
    • 18: N-[(4-ethylsulfonylphenyl)methyl]-4-[1-hydroxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzamide.
  • Figure imgb0088
     MS(ES+) m/z 472.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (t, J=5.90 Hz, 1 H) 7.90 (d, J=8.78 Hz, 2 H) 7.82 - 7.87 (m, 2 H) 7.72 (d, J=8.28 Hz, 2 H) 7.59 (d, J=8.53 Hz, 2 H) 6.40 (s, 1 H) 4.58 (d, J=5.77 Hz, 2 H) 3.25 (q, J=7.36 Hz, 2 H) 2.24 (d, J=14.56 Hz, 1 H) 1.97 (d, J=14.56 Hz, 1 H) 1.09 (t, J=7.40 Hz, 3 H) 0.72 (s, 9 H).
    • 19: N-[(4-ethylsulfonylphenyl)methyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0089
     MS(ES+) m/z 470 [M+H]+.
    • 20: N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)pentyl]benzamide.
  • Figure imgb0090
     MS(ES+) m/z 485.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.14 (t, J=5.90 Hz, 1 H) 7.91 (d, J=8.53 Hz, 2 H) 7.85 (br s, 1 H) 7.77 (m, J=8.28 Hz, 2 H) 7.65 (m, J=8.28 Hz, 2 H) 7.53 (d, J=8.28 Hz, 2 H) 6.51 (s, 1 H) 4.57 (d, J=6.02 Hz, 2 H) 2.15 - 2.24 (m, 1 H) 2.07 (tt, J=6.87, 3.54 Hz, 1 H) 1.92 - 2.01 (m, 1 H) 1.19 - 1.33 (m, 3 H) 0.75 - 0.83 (m, 4 H) 0.35 - 0.49 (m, 4 H).
    • 21: N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0091
     MS(ES+) m/z 497.2 [M+H]+.
    • 22: N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0092
     MS(ES+) m/z 510.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.33 (s, 1 H) 8.07 - 8.10 (m, 2 H) 7.84 - 7.87 (m, 2 H) 7.71 (d, J=8.28 Hz, 2 H) 7.59 (d, J=8.53 Hz, 2 H) 4.61 (d, J=6.02 Hz, 2 H) 3.48 (s, 3 H) 3.23 (d, J=7.28 Hz, 2 H) 0.77 - 0.88 (m, 1 H) 0.42 - 0.46 (m, 2 H) 0.08 - 0.15 (m, 2 H).
    • 23: N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0093
     MS(ES+) m/z 524.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (t, J=5.90 Hz, 1 H) 8.08 (d, J=8.78 Hz, 2 H) 7.86 (d, J=8.53 Hz, 2 H) 7.70 (d, J=8.28 Hz, 2 H) 7.58 (d, J=8.28 Hz, 2 H) 4.61 (d, J=6.02 Hz, 2 H) 3.61 (q, J=7.03 Hz, 2 H) 3.20 - 3.28 (m, 2 H) 1.31 (t, J=7.03 Hz, 3 H) 0.77 - 0.87 (m, 1 H) 0.41 - 0.47 (m, 2 H) 0.09 - 0.14 (m, 2 H).
    • 24: N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-propoxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0094
     MS(ES+) m/z 538.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (t, J=5.90 Hz, 1 H) 8.06 - 8.10 (m, 2 H) 7.84 - 7.87 (m, 2 H) 7.69 (m, J=8.28 Hz, 2 H) 7.58 (m, J=8.53 Hz, 2 H) 4.61 (d, J=6.02 Hz, 2 H) 3.51 (t, J=6.40 Hz, 2 H) 3.20 - 3.29 (m, 2 H) 1.72 (sxt, J=7.08 Hz, 2 H) 0.94 (t, J=7.40 Hz, 3 H) 0.77 - 0.87 (m, 1 H) 0.41 - 0.46 (m, 2 H) 0.09 - 0.13 (m, 2 H).
    • 25: 4-[1-butoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]benzamide.
  • Figure imgb0095
     MS(ES+) m/z 552.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (t, J=6.02 Hz, 1 H) 8.07 (d, J=7.96 Hz, 2 H) 7.84 - 7.88 (m, 2 H) 7.69 (m, J=8.28 Hz, 2 H) 7.59 (d, J=8.53 Hz, 2 H) 4.61 (d, J=6.02 Hz, 2 H) 3.55 (t, J=6.53 Hz, 2 H) 3.23 (d, J=7.03 Hz, 2 H) 1.64 - 1.72 (m, 2 H) 1.40 (dq, J=15.00, 7.38 Hz, 2 H) 0.91 (t, J=7.40 Hz, 3 H) 0.77 - 0.87 (m, 1 H) 0.41 - 0.47 (m, 2 H) 0.09 - 0.14 (m, 2 H).
    • 26: N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-isopropoxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0096
     MS(ES+) m/z 538.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (t, J=5.90 Hz, 1 H) 8.06 (d, J=7.89 Hz, 2 H) 7.86 (d, J=7.77 Hz, 2 H) 7.77 (d, J=8.28 Hz, 2 H) 7.59 (d, J=8.28 Hz, 2 H) 4.61 (d, J=6.02 Hz, 2 H) 3.98 (dt, J=12.05, 6.02 Hz, 1 H) 3.21 - 3.28 (m, 2 H) 1.25 (d, J=6.02 Hz, 6 H) 0.77 - 0.87 (m, 1 H) 0.41 - 0.47 (m, 2 H) 0.09 - 0.15 (m, 2 H).
    • 27: 4-[1-benzyloxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]benzamide.
  • Figure imgb0097
     MS(ES+) m/z 586.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.33 (t, J=6.02 Hz, 1 H) 8.11 (d, J=8.78 Hz, 2 H) 7.85 (d, J=7.93 Hz, 2 H) 7.75 (d, J=8.28 Hz, 2 H) 7.59 (d, J=8.28 Hz, 2 H) 7.37 - 7.47 (m, 5 H) 4.60 - 4.67 (m, 4 H) 3.20 - 3.27 (m, 2 H) 0.77 - 0.87 (m, 1 H) 0.40 - 0.46 (m, 2 H) 0.09 - 0.14 (m, 2 H).
    • 28: N-[[4-(cyclopropylmethylsulfonyl)-2-methyl-phenyl]methyl]-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0098
     MS(ES+) m/z 524.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (t, J=5.77 Hz, 1 H) 8.09 (d, J=7.27 Hz, 2 H) 7.67 - 7.74 (m, 4 H) 7.49 (d, J=8.03 Hz, 1 H) 4.56 (d, J=5.77 Hz, 2 H) 3.48 (s, 3 H) 3.20 - 3.25 (m, 2 H) 2.44 (s, 3 H) 0.78 - 0.87 (m, 1 H) 0.42 - 0.48 (m, 2 H) 0.11 - 0.16 (m, 2 H).
    • 29: N-[[4-(cyclopropylmethylsulfonyl)-2-methyl-phenyl]methyl]-4-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0099
     MS(ES+) m/z 538.2 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.21 (t, J=5.77 Hz, 1 H) 8.08 (d, J=8.53 Hz, 2 H) 7.67 - 7.73 (m, 4 H) 7.49 (d, J=8.03 Hz, 1 H) 4.56 (d, J=5.77 Hz, 2 H) 3.61 (q, J=6.78 Hz, 2 H) 3.19 - 3.25 (m, 2 H) 2.44 (s, 3 H) 1.31 (t, J=6.90 Hz, 3 H) 0.77 - 0.87 (m, 1 H) 0.42 - 0.47 (m, 2 H) 0.11 - 0.15 (m, 2 H).
    • 30: N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0100
     MS(ES+) m/z 511.0 [M+H]+.
    1 H NMR (500 MHz, DMSO-d6) δ ppm 9.31 (t, J=5.87 Hz, 1 H) 8.09 (d, J=8.56 Hz, 2 H) 7.86 (br s, 1 H) 7.77 (m, J=8.31 Hz, 2 H) 7.71 (m, J=8.31 Hz, 2 H) 7.54 (d, J=8.31 Hz, 2 H) 4.59 (d, J=5.87 Hz, 2 H) 3.48 (s, 3 H) 2.05 - 2.10 (m, 1 H) 0.36 - 0.48 (m, 4 H).
    • 31: N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0101
     MS(ES+) m/z 525.1 [M+H]+.
    1 H NMR (500 MHz, DMSO-d6) δ ppm 9.30 (br s, 1 H) 8.08 (br d, J=8.31 Hz, 2 H) 7.86 (br s, 1 H) 7.77 (m, J=7.82 Hz, 2 H) 7.70 (m, J=7.82 Hz, 2 H) 7.54 (br d, J=7.82 Hz, 2 H) 4.59 (br d, J=4.89 Hz, 2 H) 3.61 (br d, J=6.60 Hz, 2 H) 2.07 (br s, 1 H) 1.31 (br t, J=6.72 Hz, 3 H) 0.46 (br d, J=5.14 Hz, 2 H) 0.37 (br s, 2 H).
    • 32: N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-propoxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0102
     MS(ES+) m/z 539.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (br t, J=5.90 Hz, 1 H) 8.08 (br d, J=8.53 Hz, 2 H) 7.85 (br s, 1 H) 7.77 (br d, J=8.28 Hz, 2 H) 7.69 (br d, J=8.03 Hz, 2 H) 7.54 (br d, J=8.28 Hz, 2 H) 4.59 (br d, J=5.77 Hz, 2 H) 3.51 (br t, J=6.27 Hz, 2 H) 2.07 (br s, 1 H) 1.67 - 1.76 (m, 2 H) 0.94 (t, J=7.40 Hz, 3 H) 0.35 - 0.50 (m, 4 H).
    • 33: N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-methoxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzamide.
  • Figure imgb0103
     MS(ES+) m/z 512.2 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.09 (t, J=5.90 Hz, 1 H) 7.73 - 7.83 (m, 4 H) 7.62 (d, J=8.28 Hz, 2 H) 7.47 (d, J=8.28 Hz, 2 H) 4.48 (d, J=5.77 Hz, 2 H) 3.42 (d, J=2.01 Hz, 3 H) 3.12 (d, J=7.03 Hz, 2 H) 2.14 - 2.23 (m, 1 H) 2.00 - 2.06 (m, 1 H) 0.67 - 0.77 (m, 1 H) 0.64 (s, 9 H) 0.29 - 0.37 (m, 2 H) -0.01 - 0.03 (m, 2 H).
    • 34: N-[(1R)-1-[4-(cyclopropylmethylsulfonyl)phenyl]ethyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0104
    • i) To a solution of N-[(1R)-1-(4-bromophenyl)ethyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide (250 mg) in dimethyl sulfoxide (3 mL) were added sodium sulfinatomethylcyclopropane (110 mg), (+/-)-trans- cyclohexane-1,2-diamine (26 µl), copper(I) trifluoromethanesulfonate benzene complex (45 mg). The resulting mixture was heated to 125°C under microwave irradiation for 1 hour. The reaction mixture was poured into water/ether and extracted three times with ether. The combined extracts were concentrated under reduced pressure, taken up in DCM/water, filtered on a water repellent filter cartridge and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using 10% to 30% EtOAc in heptane as the eluent, followed by trituration with ether/pentane to obtain 75 mg of the expected product. MS(ES+) m/z 510.1 [M+H]+.
      1 H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (d, J=7.78 Hz, 1 H) 8.89 (br s, 1 H) 7.97 - 8.03 (m, 2 H) 7.83 - 7.88 (m, 2 H) 7.79 (d, J=8.28 Hz, 2 H) 7.65 (d, J=8.28 Hz, 2 H) 5.24 (quin, J=7.22 Hz, 1 H) 3.22 (d, J=7.28 Hz, 2 H) 1.51 (d, J=7.03 Hz, 3 H) 0.76 - 0.89 (m, 1 H) 0.40 - 0.49 (m, 2 H) 0.09 - 0.16 (m, 2 H).
    35: N-[(1S)-1-[4-(cyclopropylmethylsulfonyl)phenyl]ethyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide.
  • Figure imgb0105
     MS(ES+) m/z 510.1 [M+H]+.
    1 H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (d, J=7.78 Hz, 1 H) 8.88 (br s, 1 H) 7.99 (d, J=7.96 Hz, 2 H) 7.85 (d, J=7.84 Hz, 2 H) 7.79 (d, J=8.28 Hz, 2 H) 7.65 (d, J=8.28 Hz, 2 H) 5.24 (t, J=7.15 Hz, 1 H) 3.22 (d, J=7.03 Hz, 2 H) 1.51 (d, J=7.03 Hz, 3 H) 0.75 - 0.89 (m, 1H) 0.42 - 0.47 (m, 2 H) 0.10 - 0.14 (m, 2 H).
    • Example 36 RORγ GAL4 reporter gene assay
  • Example inhibitors 1-35 were tested for their ability to inhibit RORγ activity in a RORγ GAL4 reporter gene assay. The assay procedure and results are described below.
    • RORγ GAL4 reporter gene assay description
  • A GAL4 one-hybrid reporter system employing luciferase readout was established to determine inhibition of RORγ in 293FT cells. The RORγ ligand-binding domain (LBD) was fused to the yeast GAL4 DNA binding domain (DBD) and placed under the control of the human cytomegalovirus (CMV) immediate early promoter, using expression vector pFN26A (Promega) and standard recombinant DNA cloning methods. To serve as a control in the assay, a similar vector was generated in which the GAL4-DBD was fused to Herpes simplex virus protein 16 (VP16), a constitutive transcriptional activator.
  • To monitor the inhibitory effect of compounds on RORγ, a transcriptional reporter construct was used. The pGL4.35 vector (Promega) contains nine copies of the GAL4 Upstream Activator Sequence (UAS). This sequence drives the transcription of the luciferase reporter gene luc2P in response to binding of a fusion protein containing the GAL4 DNA binding domain, as for example expressed by the GAL4-RORγ-LBD and GAL4-VP16 expression vectors described above. To allow a GAL4 fusion protein to drive the expression of the luciferase reporter, the pGL4.35 expression vector and the appropriate GAL4 fusion protein expression vector were bulk transfected in the 293FT cells using standard transfection techniques.
  • The day after transfection, cells were plated into 96 well plates, test compound was added and the plates were incubated overnight. Subsequently, the firefly luciferase activity was quantified using luciferase detection reagent and luminescence readout.
    • Detailed assay description
  • 293FT cells (Invitrogen) were transfected with a GAL4 fusion protein expression vector (as described above) and the transcriptional reporter construct (pGL4.35, Promega). 60 µL of TransIT-293 transfection reagent (Mirus Bio) was added drop wise to 1500 µl Opti-MEM I Reduced Serum Medium (Invitrogen) and incubated at RT (RT) for 5 to 20 minutes. 1500 µL of this reagent mixture was added to 5 µg of GAL4 fusion protein expression vector and 5 µg of the transcriptional reporter construct, and incubated at RT for 20 minutes.
  • To harvest 293FT cells from a T75 flask, first the culture medium was taken off the cells. Subsequently, the cells were washed with Phosphate Buffered Saline (PBS) (Lonza), after which the PBS was removed. To dissociate the cells, 1 ml of TrypLE Express (Invitrogen) was added to the flask, followed by incubation at RT until the cells visually started to detach. Cells were collected in 5 mL of assay medium (DMEM culture medium (Lonza), 10% dialyzed FBS (Invitrogen) and Pen/Strep (Lonza)) to achieve a single cell suspension. 10x106 cells were spun down and re-suspended in 10 mL of assay medium. Subsequently, the cell suspension was added to the transfection mix tube, and then transferred as a whole to a T75 flask (Greiner), followed by overnight (16-24 hours) incubation at 37 °C and 5% CO2.
  • For compound screening, the cells were harvested (as described above) and counted. 13x106 cells were spun down, the supernatant was aspirated and the cells were re-suspended in 17.3 mL of assay medium obtaining a cell suspension of 0.75x106 cells/mL. 80 µL of cell suspension (60,000 cells) was plated per well into a white, flat bottom, tissue culture treated, 96 well screening plates (Greiner).
  • Test compounds were diluted, starting from a 10 mM dimethylsulfoxide (DMSO) stock solution, to serial dilutions in DMSO at 500x the final test concentration. Subsequently, these solutions were diluted to 5x the final test concentration in two 10-fold-dilution steps in assay medium. The final DMSO concentration of the 5x test compound solution was 1%. 20 µL of the 5x test compound solution was added to each test well of the 96 well plate previously plated with 80 µl cell suspension, resulting in the final test concentration with 0.2% DMSO.
  • The plates were incubated overnight (16-24 hours) at 37 °C and 5% CO2.
  • For the luciferase readout, the luciferase reagent (Britelite Plus, Perkin Elmer) was brought to RT. To each test well of the screening plates, 100 µL of 2.5-fold diluted Britelite Plus reagent was added, followed by incubation at RT for 10 minutes. The luciferase luminescence signal was measured using a Wallac Victor Microplate Reader (Perkin Elmer).
  • The half maximum inhibitory concentration (IC50) values for the test compounds were calculated from the luciferase signal using GraphPad Prism software (GraphPad Software).
  • Examples 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35 were found to have mean pIC50 values above 5.
  • Examples 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, and 35 were found to have mean pIC50 values above or equal to 6.
  • Examples 1, 4, 6, 7, 8, 9, 10, 11, 12, 14, 15, 22, 23, 24, 25, 26, 28, 29 and 33 were found to have mean pIC50 values above or equal to 7.
  • Unexpectedly, example 3 as a pIC50 below 5.
    • Example 37 Peripheral blood mononuclear cell (PBMC) IL-17 assay
  • Example inhibitor 5 was tested for its ability to inhibit the IL-17A production in anti-CD3/anti-CD28 stimulated peripheral blood mononuclear cells (PBMCs) isolated from human blood. The assay procedure and results are described below.
    • PBMC IL-17 assay description
  • This assay is designed to measure the levels of IL-17A secreted from anti-CD3/anti-CD28 stimulated PBMCs with the aim of measuring RORγ mediated inhibition of IL-17A production.
  • The assay medium consists of 90% RPMI 1640 (Lonza), 10% heat inactivated fetal bovin serum (FBS, Lonza) and 100 U/mL penicillin/streptomycin solution.
    • Assay description
  • Anti-CD3 antibody (BD Pharmingen) was diluted to 10 µg/ml in PBS (Lonza). 30 µL of 10 µg/ml anti-CD3 solution was added to the inner 60 wells, excluding any negative control wells, of a 96-well cell culture treated U-bottom plate (Greiner). Plates were incubated overnight (16-24 hours) at 37 °C and 5% CO2.
  • Peripheral blood mononuclear cells were separated from buffy coats (Sanquin) using Ficoll-Paque PREMIUM separation medium (GE Healthcare Life Sciences) according to manufacturer's protocol and re-suspended in assay medium at 37 °C.
  • Test compounds were diluted, starting from a 10 mM dimethylsulfoxide (DMSO) stock solution, to serial dilutions in DMSO at 200x the final test concentration. Subsequently, these solutions were diluted in two dilution steps in assay medium to 10x the final test concentration. The DMSO concentration of the 10x test compound solution was 5%.
  • Anti-CD28 antibody (BD Pharmingen) was diluted to 20 µg/mL in PBS. The PBMCs were diluted to a concentration of 2.5x106 cells/mL in assay medium at 37 °C.
  • For compound screening, the anti-CD3 coated plates were washed three times with PBS, the wells were subsequently aspirated using vacuum. To each screening well 80 µL of the PBMC suspension, 10 µL of the anti-CD28 solution and 10 µL of the 10x test compound solution was added, resulting in the final test concentration with 0.5% DMSO. All outer wells were filled with assay medium to prevent evaporation. Plates were incubated for 5 days at 37 °C and 5% CO2.
  • After incubation the plates were spun down at 1500 rpm for 4 minutes and the supernatant was collected. Subsequently, the IL-17A levels in the supernatants was determined using an IL-17 ELISA kit (human IL-17 DuoSet, R&D systems) according to manufacturer's protocol.
  • The half maximum inhibitory concentration (IC50) values for the test compounds were calculated from the IL-17A signal using GraphPad Prism software (GraphPad Software).
  • The tested example 5 was found to have a mean pIC50 value equal to 7.

Claims (10)

  1. A compound according to Formula I
    Figure imgb0106
     or a pharmaceutically acceptable salt thereof wherein:
    A11 - A14 are N or CR11, CR12, CR13, CR14, respectively, with the proviso that no more than two of the four positions A can be simultaneously N;
    R1 is C(2-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, (di)C(3-6)cycloalkylamino or (di)(C(3-6)cycloalkylC(1-3)alkyl)amino, with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl;
    R2 and R3 are independently H, F, methyl, ethyl, hydroxy, methoxy or R2 and R3 together is carbonyl, all alkyl groups, if present, optionally being substituted with one or more F;
    R4 is H or C(1-6)alkyl;
    R5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, Cl, C(1-2)alkyl,
    C(1-2)alkoxy or cyano ;
    the sulfonyl group with R1 is represented by one of R7, R8 or R9;
    the remaining R6-R14 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl, all of the alkyl groups optionally being substituted with one or more F;
    R15 is H, C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl,
    C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F, Cl, C(1-2)alkyl, C(1-2)alkoxy or cyano;
    and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl,
    C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F, Cl, C(1-2)alkyl, C(1-2)alkoxy or cyano.
  2. The compound according to claim 1 wherein :
    A11 - A14 are N or CR11, CR12, CR13, CR14, respectively, with the proviso that no more than two of the four positions A can be simultaneously N;
    R1 is C(2-6)alkyl, C(3-6)cycloalkylC(1-3)alkyl or (di)C(3-6)cycloalkylamino, with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or
    methyl;
    R2 and R3 are independently H, methyl, or R2 and R3 together is carbonyl, all alkyl groups, if present, optionally being substituted with one or more F;
    R4 is H;
    R5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)arylC(1-3)alkyl,
    C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano ;
    the sulfonyl group with R1 is represented by R8 ;
    the remaining R6-R14 are independently H, halogen, C(1-3)alkoxy or C(1-6)alkyl, all of the alkyl groups optionally being substituted with one or more F;
    R15 is C(1)alkyl substituted with one or more F or R15 is C(2-6)alkyl optionally substituted with one or more F;
    and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F.
  3. The compound according to any one of claim 1 or 2 wherein :
    A11 - A14 is CR11, CR12, CR13, CR14;
    R1 is C(2-6)alkyl, C(3-6)cycloalkylC(1-3)alkyl, (di)C(3-6)cycloalkylamino;
    R2 and R3 are independently H or methyl;
    R4 is H;
    R5 is H, C(1-6)alkyl or C(6-10)arylC(1-3)alkyl;
    the sulfonyl group with R1 is represented by R8 ;
    the remaining R6-R14 are independently H or C(1-6)alkyl;
    R15 is C(1)alkyl substituted with one or more F or R15 is C(2-6)alkyl optionally substituted with one or more F;
    and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(6-10)aryl or C(6-10)arylC(1-3)alkyl, all groups optionally substituted with one or more F.
  4. The compound according to claim 1 wherein :
    A11 or A14 is N, the remaining position A being CR11 or CR14;
    A12 and A13 are respectively CR12 and CR13 ;
    R1 is C(3-6)cycloalkylC(1-3)alkyl;
    R2 and R3 are independently H;
    R4 is H;
    R5 is H;
    the sulfonyl group with R1 is represented by R8 ;
    the remaining R6-R14 are independently H or methyl;
    R15 and R16 are C(1-6)alkyl, with all carbon atoms of alkyl groups optionally substituted with one or more F.
  5. The compound as defined in claim 1 which is selected from the group of :
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)propyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(1-hydroxy-1-methylethyl)benzamide
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)butyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)pentyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-3-methyl-1-(trifluoromethyl)butyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-hydroxy-2-methyl-1-(trifluoromethyl)propyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(1-cyclopropyl-2,2,2-trifluoro-1-hydroxy-ethyl)benzamide;
    4-(1-cyclopentyl-2,2,2-trifluoro-1-hydroxy-ethyl)-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-(2,2,2-trifluoro-1-hydroxy-1-phenyl-ethyl)benzamide;
    4-(1-benzyl-2,2,2-trifluoro-1-hydroxy-ethyl)-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-3-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]pyridine-2-carboxamide;
    N-[(4-ethylsulfonylphenyl)methyl]-4-[1-hydroxy-1-(trifluoromethyl)propyl]benzamide N-[(4-ethylsulfonylphenyl)methyl]-4-[1-hydroxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzamide;
    N-[(4-ethylsulfonylphenyl)methyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide;
    N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[1-hydroxy-1-(trifluoromethyl)pentyl]benzamide;
    N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-propoxy-1-(trifluoromethyl)ethyl]benzamide;
    4-[1-butoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-isopropoxy-1-(trifluoromethyl)ethyl]benzamide;
    4-[1-benzyloxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)-2-methyl-phenyl]methyl]-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)-2-methyl-phenyl]methyl]-4-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzamide;
    N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]benzamide;
    N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[1-ethoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzamide;
    N-[[4-(cyclopropylsulfamoyl)phenyl]methyl]-4-[2,2,2-trifluoro-1-propoxy-1-(trifluoromethyl)ethyl]benzamide;
    N-[[4-(cyclopropylmethylsulfonyl)phenyl]methyl]-4-[1-methoxy-3,3-dimethyl-1-(trifluoromethyl)butyl]benzamide;
    N-[(1R)-1-[4-(cyclopropylmethylsulfonyl)phenyl]ethyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide;
    N-[(1S)-1-[4-(cyclopropylmethylsulfonyl)phenyl]ethyl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide.
  6. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 5 or or a pharmaceutically acceptable salt thereof.
  7. Compound according to anyone of claims 1 to 5 or a pharmaceutically acceptable salt thereof for use in therapy.
  8. Compound according to anyone of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the treatment of RORγ-mediated diseases or conditions.
  9. Pharmaceutical composition which comprises a compound of Formula I according to any of claims 1 to 5 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  10. Pharmaceutical composition according to claim 8, which further comprises at least one additional therapeutically active agent.
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